Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors

ABSTRACT

and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X1, X2, X3 and X4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/858,658, filed Dec. 29, 2017, which is a continuation of U.S.application Ser. No. 15/211,702, filed Jul. 15, 2016, which claimspriority to U.S. Provisional Application Ser. No. 62/193,448, filed Jul.16, 2015 and 62/274,018, filed Dec. 31, 2015, both of which are herebyincorporated by reference in their entireties.

BACKGROUND

The present disclosure relates to novel compounds which exhibitRearranged during Transfection (RET) kinase inhibition, pharmaceuticalcompositions comprising the compounds, processes for making thecompounds, and the use of the compounds in therapy. More particularly,it relates to substituted pyrazolo[1,5-a]pyridine compounds useful inthe treatment and prevention of diseases which can be treated with a RETkinase inhibitor, including RET-associated diseases and disorders.

RET is a single-pass transmembrane receptor belonging to the tyrosinekinase superfamily that is required for normal development, maturationand maintenance of several tissues and cell types (Mulligan, L. M.,Nature Reviews Cancer, 2014, 14, 173-186). The extracellular portion ofthe RET kinase contains four calcium-dependent cadherin-like repeatsinvolved in ligand binding and a juxtamembrane cysteine-rich regionnecessary for the correct folding of the RET extracellular domain, whilethe cytoplasmic portion of the receptor includes two tyrosine kinasesubdomains.

RET signaling is mediated by the binding of a group of soluble proteinsof the glial cell line-derived neurotrophic factor (GDNF) family ligands(GFLs), which also includes neurturin (NTRN), artemin (ARTN) andpersephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev., 2005, 16,441-67). Unlike other receptor tyrosine kinases, RET does not directlybind to GFLs and requires an additional co-receptor: that is, one offour GDNF family receptor-α (GFRα) family members, which are tethered tothe cell surface by a glycosylphosphatidylinositol linkage. GFLs andGFRα family members form binary complexes that in turn bind to RET andrecruit it into cholesterol-rich membrane subdomains, which are known aslipid rafts, where RET signaling occurs.

Upon binding of the ligand-co-receptor complex, RET dimerization andautophosphorylation on intracellular tyrosine residues recruits adaptorand signaling proteins to stimulate multiple downstream pathways.Adaptor protein binding to these docking sites leads to activation ofRas-MAPK and PI3K-Akt/mTOR signaling pathways or to recruitment of theCBL family of ubiquitin ligases that functions in RET downregulation ofthe RET-mediated functions.

Aberrant RET expression and/or activity have been demonstrated indifferent cancers and in gastrointestinal disorders such as irritablebowel syndrome (IBS).

SUMMARY OF THE INVENTION

It has now been found that substituted pyrazolo[1,5-a]pyridine compoundsare inhibitors of RET kinase, and are useful for treating diseases suchas proliferative diseases including cancers.

Accordingly, provided herein is a compound of the General Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein A, B,D, E, X¹, X², X³ and X⁴ are as defined herein.

Also provided herein is a pharmaceutical composition comprising acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, in admixture with a pharmaceutically acceptable diluentor carrier.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof as defined herein.

Also provided herein is a method of treating a RET-associated disease ordisorder in a patient in need of such treatment, the method comprisingadministering to the patient a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof as definedherein.

Also provided herein is a method of treating cancer and/or inhibitingmetastasis associated with a particular cancer in a patient in need ofsuch treatment, the method comprising administering to the patient atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein.

Also provided herein is a method of treating irritable bowel syndrome(IBS) and/or pain associated with IBS in a patient in need of suchtreatment, the method comprising administering to the patient atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein.

Also provided is a method of providing supportive care to a cancerpatient, including preventing or minimizing gastrointestinal disorders,such as diarrhea, associated with treatment, including chemotherapeutictreatment, the method comprising administering to the patient atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein.

Also provided herein is a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof as defined herein for use in therapy.

Also provided herein is a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein for use in the treatment of cancerand/or inhibiting metastasis associated with a particular cancer.

Also provided herein is a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein for use in the treatment ofirritable bowel syndrome (IBS) or pain associated with IBS.

Also provided is a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof as defined herein for use providing supportive care to a cancerpatient, including preventing or minimizing gastrointestinal disorders,such as diarrhea, associated with treatment, including chemotherapeutictreatment.

Also provided herein is a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof for use in theinhibition of RET kinase activity.

Also provided herein is a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof as defined herein, for use in the treatment of aRET-associated disease or disorder.

Also provided herein is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the treatment of cancer and/orinhibiting metastasis associated with a particular cancer.

Also provided herein is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the treatment of irritable bowelsyndrome (IBS) or pain associated with IBS.

Also provided herein is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for providing supportive care to acancer patient, including preventing or minimizing gastrointestinaldisorders, such as diarrhea, associated with treatment, includingchemotherapeutic treatment.

Also provided herein is a use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, as defined hereinin the manufacture of a medicament for the inhibition of RET kinaseactivity.

Also provided herein is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, as defined herein,in the manufacture of a medicament for the treatment of a RET-associateddisease or disorder.

Also provided herein is a method for treating cancer in a patient inneed thereof, the method comprising (a) determining if the cancer isassociated with a dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., aRET-associated cancer); and (b) if the cancer is determined to beassociated with a dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., aRET-associated cancer), administering to the patient a therapeuticallyeffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof.

Also provided herein is a pharmaceutical combination for treating cancer(e.g., a RET-associated cancer, such as a RET-associated cancer havingone or more RET inhibitor resistance mutations) in a patient in needthereof, which comprises (a) a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, (b) an additionaltherapeutic agent, and (c) optionally at least one pharmaceuticallyacceptable carrier, wherein the compound of General Formula I or thepharmaceutically acceptable salt or solvate thereof and the additionaltherapeutic are formulated as separate compositions or dosages forsimultaneous, separate or sequential use for the treatment of cancer,wherein the amounts of the compound of General Formula I or apharmaceutically acceptable salt or solvate thereof and of theadditional therapeutic agent are together effective in treating thecancer. Also provided herein is a pharmaceutical composition comprisingsuch a combination. Also provided herein is the use of such acombination for the preparation of a medicament for the treatment ofcancer. Also provided herein is a commercial package or productcomprising such a combination as a combined preparation forsimultaneous, separate or sequential use; and to a method of treatmentof cancer a patient in need thereof.

Also provided herein is a method for reversing or preventing acquiredresistance to an anticancer drug, comprising administering atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, to a patient atrisk for developing or having acquired resistance to an anticancer drug.In some embodiments, the patient is administered a dose of theanticancer drug (e.g., at substantially the same time as a dose of acompound of Formula I or a pharmaceutically acceptable salt or solvatethereof is administered to the patient).

Also provided herein is a method of delaying and/or preventingdevelopment of cancer resistant to an anticancer drug in an individual,comprising administering to the individual an effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, before, during, or after administration of an effectiveamount of the anticancer drug.

Also provided herein is a method of treating an individual with cancerwho has an increased likelihood of developing resistance to ananticancer drug, comprising concomitantly administering to theindividual (a) an effective amount of a compound of General Formula Iand (b) an effective amount of the anticancer drug.

Also provided are methods of treating an individual with aRET-associated cancer that has one or more RET inhibitor resistancemutations that increase resistance of the cancer to a RET inhibitor thatis not a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof (e.g., a substitution at amino acid position804, e.g., V804M, V804L, or V804E), that include administering acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, before, during, or after administration of anotheranticancer drug (e.g., a RET kinase inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof).

Also provided are methods of treating an individual with aRET-associated cancer that include administering a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof,before, during, or after administration of another anticancer drug(e.g., a RET kinase inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof).

Also provided herein is a method for treating irritable bowel syndrome(IBS) in a patient in need thereof, the method comprising (a)determining if the IBS is associated with a dysregulation of a RET gene,a RET kinase, or expression or activity or level of any of the same; and(b) if the IBS is determined to be associated with a dysregulation of aRET gene, a RET kinase, or expression or activity or level of any of thesame, administering to the patient a therapeutically effective amount ofa compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof.

Also provided herein is a pharmaceutical combination for treatingirritable bowel syndrome (IBS) in a patient in need thereof, whichcomprises administering (a) a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, (b) an additionaltherapeutic agent, and (c) optionally at least one pharmaceuticallyacceptable carrier, for simultaneous, separate or sequential use for thetreatment of IBS, wherein the amounts of the compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof and of theadditional therapeutic agent are together effective in treating the IBS.Also provided herein is a pharmaceutical composition comprising such acombination. Also provided herein is the use of such a combination forthe preparation of a medicament for the treatment of the IBS. Alsoprovided herein is a commercial package or product comprising such acombination as a combined preparation for simultaneous, separate orsequential use; and to a method of treatment of the IBS a patient inneed thereof.

Also provided herein is a process for preparing a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof obtained by aprocess of preparing the compound as defined herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein is a compound of the General Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X¹ is CH, CCH₃, CF, CCl or N;

X² is CH, CF or N;

X³ is CH, CF or N;

X⁴ is CH, CF or N;

wherein zero, one or two of X¹, X², X³ and X⁴ is N;

A is H, Cl, CN, Br, CH₃, CH₂CH₃ or cyclopropyl;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl, hydroxyC1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl,cyanoC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C1-C4 alkoxy)CH₂C(═O)—,(C1-C4 alkoxy)C(═O)C1-C3 alkyl, C3-C6 cycloalkyl, (R^(a)R^(b)N)C1-C6alkyl, (R^(a)R^(b)N)C(═O)C1-C6 alkyl, (C1-C6 alkylSO₂)C1-C6 alkyl,hetCyc^(a) and 4-methoxybenzyl;

R^(a) and R^(b) are independently H or C1-C6 alkyl;

hetCyc^(a) is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N and O, wherein the heterocyclic ring is optionallysubstituted with halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6alkyl, trifluoroC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, di(C1-C3alkyl)NCH₂C(═O), (C1-C6 alkoxy)C(═O) or (C1-C6 alkoxy)CH₂C(═O);

D is hetCyc¹, hetCyc², hetCyc³ or hetCyc⁹;

hetCyc¹ is a 4-6 membered heterocyclic ring having 1-2 ring atomsselected from N and O, wherein the heterocyclic ring is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C1-C3 alkyl, fluoroC1-C3 alkyl, difluoroC1-C3alkyl, trifluoroC1-C3 alkyl and OH, or said heterocyclic ring issubstituted with a C3-C6 cycloalkylidene ring, or said heterocyclic ringis substituted with an oxo group;

hetCyc² is a 7-8 membered bridged heterocyclic ring having 1-3 ringheteroatoms independently selected from N and O, wherein theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C3alkyl;

hetCyc³ is a 7-11 membered heterospirocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein the ring isoptionally substituted with C1-C3 alkyl;

hetCyc⁹ is a fused 9-10 membered heterocyclic ring having 1-3 ringnitrogen atoms and optionally substituted with oxo;

E is

(a) hydrogen,

(b) OH,

(c) R^(a)R^(b)N—, wherein R^(a) is H or C1-C6 alkyl and R^(b) is H,C1-C6 alkyl or phenyl;

(d) C1-C6 alkyl optionally substituted with one to three fluoros,

(e) hydroxyC1-C6 alkyl- optionally substituted with one to threefluoros,

(f) C1-C6 alkoxy optionally substituted with one to three fluoros,

(g) hydroxy(C1-C6 alkoxy) optionally substituted with one to threefluoros,

(h) (C1-C6 alkoxy)hydroxy C1-C6 alkyl- optionally substituted with oneto three fluoros,

(i) (C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros,

(j) (hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros,

(k) (C1-C6 alkoxy)C(═O)—,

(l) (C1-C6 alkoxy)(C1-C6 alkyl)C(═O)—,

(m) HC(═O)—,

(n) Cyc¹,

(o) Cyc¹C(═O)—,

(p) Cyc¹(C1-C6 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or more groups independently selected from thegroup consisting of OH, fluoro, C1-C3 alkoxy and R^(c)R^(d)N—, whereR^(c) and R^(d) are independently H or C1-C6 alkyl,

(q) hetCyc⁴,

(r) hetCyc⁴C(═O)—,

(s) hetCyc⁴(C1-C3 alkyl)C(═O)—,

(t) (hetCyc⁴)C(═O)C1-C2 alkyl-,

(u) hetCyc⁴C(═O)NH—,

(v) Ar²,

(w) Ar²C(═O)—,

(x) Ar²C1-C6 alkyl-,

(y) (Ar²)hydroxy C2-C6 alkyl-,

(z) Ar²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f)are independently H or C1-C6 alkyl, or R^(e) and R^(f) together with thenitrogen to which they are attached form a 5-6 membered azacyclic ringoptionally having an additional ring heteroatom selected from N and O,

(aa) hetAr²C(═O)—,

(bb) (hetAr²)hydroxyC2-C6 alkyl-,

(cc) hetAr²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N—, where R^(e) and R^(f) are independently H or C1-C6 alkyl,or R^(e) and R^(f) together with the nitrogen to which they are attachedform a 5-6 membered azacyclic ring optionally having an additional ringheteroatom selected from N and O,

(dd) R¹R²NC(═O)—,

(ee) R¹R²N(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with phenyl,

(ff) R¹R²NC(═O)C1-C2 alkyl-,

(gg) R¹R²NC(═O)NH—,

(hh) CH₃SO₂(C1-C6 alkyl)C(═O)—,

(ii) (C1-C6 alkyl)SO₂—,

(jj) (C3-C6 cycloalkyl)CH₂SO₂—,

(kk) hetCyc⁵-SO₂—,

(ll) R⁴R⁵NSO₂—,

(mm) R⁶C(═O)NH—,

(nn) hetCyc⁶;

(oo) hetAr²C1-C6 alkyl-,

(pp) (hetCyc⁴)C1-C6 alkyl-,

(qq) (C1-C6 alkoxy)C1-C6 alkyl- wherein said alkoxy portion isoptionally substituted with 1-3 fluoros,

(rr) (C3-C6 cycloalkoxy)C1-C6 alkyl-,

(ss) (C3-C6 cycloalkyl)C1-C6 alkyl- wherein said cycloalkyl isoptionally substituted with 1-2 fluoros,

(tt) (R^(g)R^(h)N)C1-C6 alkyl- wherein R^(g) and R^(h) are independentlyH or C1-C6 alkyl,

(uu) Ar²—O—,

(vv) (C1-C6 alkylSO₂)C1-C6 alkyl-,

(ww) (C1-C6 alkoxy)C(═O)NHC1-C6 alkyl-,

(xx) (C3-C6 cycloalkoxy)C(═O)—,

(yy) (C3-C6 cycloalkyl)SO₂— wherein said cycloalkyl is optionallysubstituted with C1-C6 alkyl,

(zz) Ar⁴CH₂OC(═O)—,

(aaa) (N—(C1-C3 alkyl)pyridinonyl)C1-C3 alkyl-, and

(bbb) (Ar⁴SO₂)C1-C6 alkyl-;

Cyc¹ is a C3-C6 cycloalkyl, wherein (a) the cycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of OH, halogen, C1-C6 alkoxy, CN, hydroxyC1-C6alkyl, (C1-C6 alkoxy)C1-C6 alkyl, and C1-C6 alkyl optionally substitutedwith 1-3 fluoros, or (b) the cycloalkyl is substituted with phenyl,wherein the phenyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C1-C3 alkyl, C1-C3 alkoxy and CF, or (c) the cycloalkyl issubstituted with a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N and O, wherein the heteroarylring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C3alkyl, C1-C3 alkoxy and CF₃;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C6alkyl, C1-C6 alkoxy (optionally substituted with 1-3 fluoros),fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, CN, a 5-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, and R^(i)R^(j)N— where R^(i) and R^(j) areindependently H and C1-C6 alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, C1-C6 alkyl, C1-C6 alkoxy (optionally substitutedwith 1-3 fluoros), fluoroC1-C6 alkyl, difluoroC1-C6 alkyl,trifluoroC1-C6 alkyl, hydroxyC1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6alkoxy)C1-C6 alkyl, CN and R′R″N— where R′ and R″ are independently H orC1-C3 alkyl;

hetCyc⁴ is (a) a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N, O and S wherein said S isoptionally oxidized to SO₂, (b) a 7-8 membered bridged heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, (c) a6-12 membered fused bicyclic heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallyindependently substituted with 1-2 C1-C6 alkyl subsitutents, or (d) a7-10 membered spirocyclic heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein each of the heterocyclicrings is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, OH, CN,C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy,(C1-C6 alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6 alkyl)C(═O)—, a 5-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, and phenyl wherein said phenyl is optionallysubstituted with one or more substituents selected from halogen, C1-C6alkyl and C1-C6 alkoxy;

hetCyc⁵ is a 5-6 membered heterocyclic ring having a ring heteroatomselected from O and N;

hetCyc⁶ is a 5 membered heterocyclic ring having one or two ringheteroatoms independently selected from N and O, wherein the ringsubstituted with oxo and wherein the ring is further optionallysubstituted with one or more substituents independently selected fromthe group consisting of OH and C1-C6 alkyl;

R¹ is H, C1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl;

R² is H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl (optionally substituted with 1-3 fluoros), Cyc³,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O),hetCyc⁷, Ar³, Ar³C1-C3 alkyl-, hydroxyC1-C6 alkoxy or (C3-C6cycloalkyl)CH₂O—;

Cyc³ is a 3-6 membered carbocyclic ring optionally substituted with 1-2groups independently selected from the group consisting of C1-C6 alkoxy,OH and halogen;

hetCyc⁷ is a 5-6 membered heterocyclic ring having a ring heteroatomselected from O and N wherein the ring is optionally substituted withC1-C6 alkyl;

Ar³ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy,fluoroC1-C3 alkyl, difluoroC1-C3 alkyl and trifluoroC1-C3 alkyl;

R⁴ and R⁵ are independently H or C1-C6 alkyl;

R⁶ is C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkoxy)C1-C6alkyl, phenyl or hetCyc⁸;

hetCyc⁸ is a 5-6 membered heterocyclic ring having a ring heteroatomselected from O and N, wherein the heterocyclic ring is optionallysubstituted with C1-C6 alkyl; and

Ar⁴ is phenyl optionally substituted with one or more halogens.

As used herein, the word “a” before a noun represents one or more of theparticular noun. For example, the phrase “a cell” represents “one ormore cells.”

For complex chemical names employed herein, a substituent group istypically named before the group to which it attaches. For example,methoxyethyl group comprises an ethyl backbone with a methoxysubstituent.

The term “halogen” means —F (sometimes referred to herein as “fluoro” or“fluoros”), —Cl, —Br and —I.

The term “azacyclic ring” as used herein refers to a saturatedheterocyclic ring having a ring nitrogen atom.

The terms “C1-C3 alkyl” and “C1-C6 alkyl” as used herein refer tosaturated linear or branched-chain monovalent hydrocarbon radicals ofone to three or one to six carbon atoms, respectively. Examples include,but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl,isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, and hexyl.

The terms “C1-C3 alkoxy”, “C1-C4 alkoxy” and “C1-C6 alkoxy”, as usedherein refer to saturated linear or branched-chain monovalent alkoxyradicals of one to three, one to four or one to six carbon atoms,respectively, wherein the radical is on the oxygen atom. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

The term “fluoroC1-C6 alkyl” as use herein refers to saturated linear orbranched-chain monovalent radicals of one to six carbon atoms, whereinone of the hydrogen atoms is replaced by fluorine. Examples includefluoromethyl, 3-fluoropropyl and 2-fluoroethyl.

The term “difluoroC1-C6 alkyl” as use herein refers to saturated linearor branched-chain monovalent radicals of one to six carbon atoms,wherein two of the hydrogen atoms are replaced by fluorine. Examplesinclude difluoromethyl, 2,2-difluoroethyl, and 1,3-difluoroprop-2-yl,

The term “trifluoroC1-C6 alkyl” as used herein refers to saturatedlinear or branched-chain monovalent radicals of one to six carbon atoms,wherein three of the hydrogen atoms are replaced by fluorine. Examplesinclude trifluoromethyl, 2,2,2-trifluoroethyl, and3,3,3-trifluoropropyl.

The term “(C1-C6 alkoxy)C1-C6 alkyl” as used herein refers to saturatedlinear or branched-chain monovalent radicals of one to six carbon atoms,wherein one of the carbon atoms is substituted with a (C1-C6 alkoxy)group as defined herein. Examples include methoxymethyl (CH₃OCH₂—) andmethoxyethyl (CH₃OCH₂CH₂—).

The term “hydroxyC1-C6 alkyl” as used herein refers to saturated linearor branched-chain monovalent alkyl radicals of one to six carbon atoms,wherein one of the carbon atoms is substituted with a hydroxy group.

The term “hydroxyC1-C6 alkoxy” as used herein refers to saturated linearor branched-chain monovalent alkoxy radicals of one to six carbon atoms,wherein one of the carbon atoms is substituted with a hydroxy group.

The term “(C1-C6 alkoxy)hydroxyC1-C6 alkyl” as used herein refers to ahydroxy (C1-C6 alkyl) radical as defined herein, wherein one of thecarbon atoms is substituted with a C1-C6 alkoxy group as defined herein.

The term “Cyc¹(C1-C6 alkyl)” as used herein refers to saturated linearor branched-chain monovalent alkyl radicals of one to six carbon atoms,wherein one of the carbon atoms is substituted with a 3-6 memberedcycloalkyl ring.

The term “Cyc¹(C1-C6 alkyl)C(═O)—” as used herein refers to a (C1-C6alkyl)C(═O)— group, wherein the C1-C6 alkyl is a saturated linear orbranched-chain monovalent radical of one to six carbon atoms and whereinone of the carbon atoms of the C1-C6 alkyl portion is substituted with aC3-C6 cycloalkyl group.

The term “Ar²C1-C6 alkyl” as used herein refers to C1-C6 alkyl radicalas defined herein one of the carbon atoms of the alkyl portion issubstituted with Ar².

The term “(Ar²)hydroxy C2-C6 alkyl” as used herein refers to ahydroxyC1-C6 alkyl radical as defined herein wherein one of the carbonatoms of the alkyl portion is substituted with Ar².

The term “Ar²(C1-C3 alkyl)C(═O)—” as used herein refers to a C1-C3alkyl(C═O)— radical wherein the C1-C3 alkyl portion is a saturatedlinear or branched-chain monovalent alkyl radicals of one to threecarbon atoms, wherein one of the carbon atoms is substituted with Ar².

The term “(hetAr²)hydroxy C2-C6 alkyl” as used herein refers to ahydroxyC1-C6 alkyl radical as defined herein wherein one of the carbonatoms is substituted with hetAr².

The term “hetAr²(C1-C3 alkyl)C(═O)—” as used herein refers to a C1-C3alkyl(C═O)— radical wherein the C1-C3 alkyl portion is a saturatedlinear or branched-chain monovalent alkyl radical of one to three carbonatoms, wherein one of the carbon atoms is substituted with hetAr².

The term “R¹R²NC(═O)C1-C2 alkyl” as used herein refers to a C1-C2 alkylradical wherein one of the carbon atoms is substituted with aR¹R²NC(═O)— group.

The term “R¹R²N(C1-C3 alkyl)C(═O)—” as used herein refers to a C1-C3alkyl(C═O)— radical wherein the C1-C3 alkyl portion is a saturatedlinear or branched-chain monovalent alkyl radicals of one to threecarbon atoms, wherein one of the carbon atoms is substituted with aR¹R²N— group, wherein R¹ and R² are as defined for General Formula I.

The term “(C1-C6 alkylSO₂)C1-C6 alkyl” as used herein as used hereinrefers to saturated linear or branched-chain monovalent radicals of oneto six carbon atoms, wherein one of the carbon atoms is substituted witha (C1-C6 alkyl)SO₂— group (e.g., a (CH₃)₂CH₂SO₂— group).

The term “(Ar⁴SO₂)C1-C6 alkyl” as used herein as used herein refers tosaturated linear or branched-chain monovalent radicals of one to sixcarbon atoms, wherein one of the carbon atoms is substituted with a(Ar⁴)SO₂— group.

The term “bridged heterocyclic ring” as used herein refers to a bicyclicheterocycle, wherein two common nonadjacent carbon atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Examples ofbridged heterocyclic ring systems include3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane,3,8-diazabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane,8-azabicyclo[3.2.1]octane and 7-azabicyclo[2.2.1]heptane.

The term “spirocyclic ring” as used herein refers to a group having tworings joined by a spirocyclic linkage through a common single carbonatom, wherein each ring is a 4-7-membered ring (including the commoncarbon atom).

The term “heterospirocyclic” as used herein refers to a group having tworings joined by a spirocyclic linkage through a carbon atom, whereineach ring has 4 to 6 ring atoms (with one ring atom being common to bothrings), and wherein 1 or 2 of the ring atoms is a heteroatom selectedfrom the group consisting of N and O, provided that the heteroatoms arenot adjacent. Examples include 2,6-diazaspiro[3.3]heptane,2,5-diazaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane,6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[4.4]nonane,7-oxa-2-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane,2,7-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.5]nonane,2,5-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.4]octane,1,7-diazaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane,2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane,2,6-diazaspiro[4.5]decane, 1,7-diazaspiro[3.5]nonane,2,7-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.5]nonane,1,8-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane, 1,7-diazaspiro[4.5]decane,2,9-diazaspiro[5.5]undecane, and 7-azaspiro[3.5]nonane.

As used herein, the term “cycloalkylidine ring” refers to a divalentcarbocyclic ring. The suffix “ylidine” refers to bivalent radicalderived from a saturated hydrocarbon by removal of two hydrogen atomsfrom the same carbon atom.

The term “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The term “tautomer” as used herein refers to compounds whose structuresdiffer markedly in arrangement of atoms, but which exist in easy andrapid equilibrium, and it is to be understood that compounds providedherein may be depicted as different tautomers, and when compounds havetautomeric forms, all tautomeric forms are intended to be within thescope of the invention, and the naming of the compounds does not excludeany tautomer.

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom. For example, a non-limiting example of a heterocyclic ringthat is substituted with an oxo group is the structure:

The term “(N—(C1-C3 alkyl)pyridinonyl)C1-C3 alkyl” as used herein refersto a C1-C3 alkyl radical as defined herein where one of the carbon atomsof the alkyl portion is substituted with a 2-oxo-1,2-dihydropyridinethat is substituted on the pyridone nitrogen with 1-3 carbons. Examplesinclude 1-methyl-1,2-dihydropyridin-2-one.

In certain embodiments of Formula I, X¹ is CH, CCH₃, CF, or CCl, X² isCH or CF, X³ is CH or CF, and X⁴ is CH or CF. In certain embodiments,each of X¹, X², X³ and X⁴ is CH.

In certain embodiments of Formula I, X¹ is CH, CCH₃, CF, CCl or N, X² isCH, CF or N, X³ is CH, CF or N, and X⁴ is CH, CF or N, wherein one ofX¹, X², X³ and X⁴ is N.

In certain embodiments of Formula I, X¹ is N, X² is CH or CF, X³ is CHor CF, and X⁴ is CH or CF. In certain embodiments, X¹ is N, and X², X³and X⁴ are CH.

In certain embodiments of Formula I, X¹ is CCH₃, X² is CH, CF or N; X³is CH, CF or N, and X⁴ is CH, CF or N; wherein one of X², X³ and X⁴ isN. In certain embodiments, X¹ is CCH₃, X² is N; X³ is CH or CF, and X⁴is CH or CF. In certain embodiments, X¹ is CCH₃, X² is N, and X³ and X⁴are CH.

In certain embodiments of Formula I, X¹ is CH, CCH₃, CF, CCl or N; X² isCH, CF or N; X³ is CH, CF or N; and X⁴ is CH, CF or N, wherein two ofX¹, X², X³ and X⁴ are N.

In certain embodiments of Formula I, X¹ and X² are N, and X³ and X⁴ areCH or CF. In certain embodiments, X¹ and X² are N, and X³ and X⁴ are CH.

In certain embodiments, X¹ and X³ are N, and X² and X⁴ are CH or CF. Incertain embodiments, X¹ and X³ are N, and X² and X⁴ are CH.

In certain embodiments, A is H, Cl, CN, Br, CH₃, or CH₂CH₃.

In certain embodiments, A is H.

In certain embodiments, A is Cl.

In certain embodiments, A is CN.

In certain embodiments, A is Br.

In certain embodiments, A is CH₃.

In certain embodiments, A is CH₃CH₂—.

In certain embodiments, A is cyclopropyl.

In certain embodiments, B is hetAr¹ where hetAr¹ is a 5-memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O, wherein the heteroaryl ring is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, C1-C6 alkyl, hydroxyC1-C6 alkyl, fluoroC1-C6alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, cyanoC1-C6 alkyl,(C1-C6 alkoxy)C1-C6 alkyl, (C1-C4 alkoxy)CH₂C(═O)—, (C1-C4alkoxy)C(═O)C1-C3 alkyl, C3-C6 cycloalkyl, (R^(a)R^(b)N)C1-C6 alkyl,(R^(a)R^(b)N)C(═O)C1-C6 alkyl, (C1-C6 alkylSO₂)C1-C6 alkyl, hetCyc^(a)and 4-methylbenzyl.

In certain embodiments, B is hetAr¹ where hetAr¹ is a 5-memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O, wherein the heteroaryl ring is optionally substituted withone or more substituents independently selected from the groupconsisting of C1-C6 alkyl fluoroC1-C6 alkyl, difluoroC1-C6 alkyl,trifluoroC1-C6 alkyl and hydroxyC1-C6 alkyl.

In certain embodiments, hetAr¹ is pyrazolyl, imidazolyl, oxazolyl,isoxazolyl thiazolyl, thiadiazolyl, triazolyl or oxadiazolyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C1-C6 alkyl, hydroxyC1-C6 alkyl,fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, cyanoC1-C6alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C1-C4 alkoxy)CH₂C(═O)—, (C1-C4alkoxy)C(═O)C1-C3 alkyl, C3-C6 cycloalkyl, (R^(a)R^(b)N)C1-C6 alkyl,(R^(a)R^(b)N)C(═O)C1-C6 alkyl, (C1-C6 alkylSO₂)C1-C6 alkyl, hetCyc^(a)and 4-methoxybenzyl.

In certain embodiments, B is pyrazolyl, imidazolyl, oxazolyl orisoxazolyl optionally substituted with one or more substituentsindependently selected from C1-C6 alkyl, fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, hydroxyC1-C6 alkyl, C3-C6cycloalkyl, hetCyc^(a) and 4-methoxybenzyl.

In certain embodiments, B is pyrazolyl or imidazolyl optionallysubstituted with one or more substituents independently selected fromC1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6alkyl and hydroxyC1-C6 alkyl.

In certain embodiments, B is pyrazolyl optionally substituted with oneor more substituents independently selected from C1-C6 alkyl.

Non-limiting examples of hetAr¹ include the structures:

In certain embodiments, D is hetCyc¹ where hetCyc¹ is a 4-6 memberedheterocyclic ring having 1-2 ring atoms selected from N and O, whereinthe heterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C3alkyl, fluoroC1-C3 alkyl, difluoroC1-C3 alkyl, trifluoroC1-C3 alkyl andOH, or the heterocyclic ring is substituted with a C3-C6 cycloalkylidenering, or said heterocyclic ring is substituted with an oxo group.

In certain embodiments, hetCyc¹ is a pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or azetidinyl ring optionally substituted withone or more substituents independently selected from the groupconsisting of C1-C3 alkyl, fluoroC1-C3 alkyl, difluoroC1-C3 alkyl,trifluoroC1-C3 alkyl and OH, or hetCyc¹ is a piperazinyl ringsubstituted with a C3-C6 cycloalkylidene ring, or hetCyc¹ is apiperazinyl ring substituted with an oxo group.

In certain embodiments, hetCyc¹ is a pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or azetidinyl ring optionally substituted witha group selected from C1-C3 alkyl and trifluoroC1-C3 alkyl, or thehetCyc¹ is substituted with a C3-C6 cycloalkylidene ring, or hetCyc¹ ispiperazin-2-onyl. In certain embodiments, hetCyc¹ is a pyrrolidinyl,piperidinyl, piperazinyl or morpholinyl ring optionally substituted witha group selected from C1-C3 alkyl and trifluoroC1-C3 alkyl, or thehetCyc¹ is substituted with a C3-C6 cycloalkylidene ring.

In certain embodiments, hetCyc¹ is piperidinyl or piperazinyl.

In certain embodiments, hetCyc¹ is piperazinyl.

Non-limiting examples of D when represented by hetCyc¹ include thestructures:

where the asterisk indicates the point of attachment to the E group.

In one embodiment of the D-E group, D is hetCyc¹ and E is hydrogen.Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is OH. In one embodiment, hetCyc¹is a 5-6 membered heterocyclic ring having a ring nitrogen atom, whereinthe ring is optionally substituted with trifluorol-C3 alkyl.Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is R^(a)R^(b)N— where R^(a) is Hor C1-C6 alkyl and R^(b) is H, C1-C6 alkyl or phenyl. In one embodiment,hetCyc¹ is a 6 membered heterocyclic ring having a ring nitrogen atom,wherein the ring is optionally substituted with C1-C3 alkyl.Non-limiting examples include the structures:

In one embodiment of the D-E group, D is hetCyc¹ and E is C1-C6 alkyloptionally substituted with one to three fluoros. Non-limiting examplesinclude the structures:

In one embodiment, D is hetCyc¹ and E is hydroxyC1-C6 alkyl optionallysubstituted with one to three fluoros. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc¹ and E is C1-C6 alkoxy optionallysubstituted with one to three fluoros. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc¹ and E is hydroxy(C1-C6 alkoxy)optionally substituted with one to three fluoros. A non-limitingexamples include the structure:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkoxy)hydroxy C1-C6alkyl optionally substituted with one to three fluoros. A non-limitingexample includes the structure:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkyl)C(═O)— optionallysubstituted with one to three fluoros. In one embodiment, hetCyc¹ is a6-membered heterocyclic ring having 1-2 ring nitrogen atoms, wherein theheterocyclic ring is optionally substituted with cyclopropyl.Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is (hydroxy C1-C6 alkyl)C(═O)—optionally substituted with one to three fluoros. In one embodiment,hetCyc¹ is a 6-membered heterocyclic ring having a ring nitrogen atom,wherein the heterocyclic ring is optionally substituted withcyclopropyl. Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkoxy)C(═O)—. In oneembodiment, hetCyc¹ is a 6-membered heterocyclic ring having 1-2 ringnitrogen atoms, wherein the heterocyclic ring is optionally substitutedwith cyclopropyl or C1-C3 alkyl. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkoxy)(C1-C6alkyl)C(═O)—. Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is HC(═O)—. A non-limiting exampleis the structure:

In one embodiment, D is hetCyc¹ and E is Cyc¹, Cyc¹C(═O)—, or Cyc¹(C1-C6alkyl)C(═O)—, wherein in each instance, Cyc¹ is a C3-C6 cycloalkyl,wherein (a) Cyc¹ is optionally substituted with one or more substituentsindependently selected from the group consisting of OH, halogen, C1-C6alkoxy, CN, hydroxyC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, and C1-C6alkyl optionally substituted with 1-3 fluoros, or (b) Cyc¹ issubstituted with phenyl, wherein the phenyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C1-C3 alkyl, C1-C3 alkoxy and CF, or (c) Cyc¹ issubstituted with a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N and O, wherein the heteroarylring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C3alkyl, C1-C3 alkoxy and CF₃.

In one embodiment, D is hetCyc¹ and E is Cyc¹, where Cyc¹ is a C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one ormore substituents independently selected from the group consisting ofOH, halogen, C1-C6 alkoxy, CN, hydroxyC1-C6 alkyl, (C1-C6 alkoxy)C1-C6alkyl, and C1-C6 alkyl optionally substituted with 1-3 fluoros. In oneembodiment, Cyc¹ is a C3-C6 cycloalkyl optionally substituted with OH.Non-limiting examples when D is hetCyc¹ and E is Cyc¹ include thestructures:

In one embodiment, D is hetCyc¹ and E is Cyc¹C(═O)— where Cyc¹ is asdefined for General Formula I. In one embodiment, Cyc¹ is a C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one ormore substituents independently selected from the group consisting of OHor halogen. In one embodiment, the cycloalkyl is substituted withphenyl. Non-limiting examples when D is hetCyc¹ and E is Cyc¹C(═O)—include the structures:

In one embodiment, D is hetCyc¹ and E is Cyc¹(C1-C6 alkyl)C(═O)— whereinthe alkyl portion is optionally substituted with one or more groupsindependently selected from the group consisting of OH, fluoro, C1-C3alkoxy and R^(c)R^(d)N— where R^(c) and R^(d) are independently H orC1-C6 alkyl. In one embodiment, Cyc¹ is a C3-C6 cycloalkyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of OH, halogen, C1-C6 alkoxy, CN, hydroxyC1-C6alkyl, (C1-C6 alkoxy)C1-C6 alkyl, and C1-C6 alkyl optionally substitutedwith 1-3 fluoros. In one embodiment, the alkyl portion of Cyc¹(C1-C6alkyl)C(═O)— is unsubstituted. In one embodiment, Cyc¹ is unsubstituted.A non-limiting example when D is hetCyc¹ and E is Cyc¹(C1-C6alkyl)C(═O)— is the structure:

In one embodiment, D is hetCyc¹ and E is hetCyc⁴, hetCyc⁴C(═O)—,hetCyc⁴(C1-C3 alkyl)C(═O)—, (hetCyc⁴)C(═O)C1-C2 alkyl, orhetCyc⁴C(═O)NH—, wherein in each instance, hetCyc⁴ is as defined forGeneral Formula I.

In one embodiment, D is hetCyc¹ and E is hetCyc⁴, hetCyc⁴C(═O)—,hetCyc⁴(C1-C3 alkyl)C(═O)—, (hetCyc⁴)C(═O)C1-C2 alkyl, orhetCyc⁴C(═O)NH—, wherein in each instance hetCyc⁴ is (a) a 5-6 memberedheterocyclic ring, (b) a 7-8 membered bridged heterocyclic ring, (c) a8-12 membered fused bicyclic heterocyclic ring, or (d) a 7-10 memberedspirocyclic heterocyclic ring, wherein each of the heterocyclic ringshas 1-2 ring heteroatoms independently selected from N and O, andwherein each of the heterocyclic rings is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with1-3 fluoros), C1-C6 alkoxy and (C1-C6 alkoxy)C1-C6 alkyl.

In one embodiment, hetCyc⁴ is tetrahydrofuranyl, pyrrolidinyl,piperidinyl, morpholinyl or tetrahydro-2H-thiopyranyl 1,1-dioxideoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, OH, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy and (C1-C6alkoxy)C1-C6 alkyl.

In one embodiment, D is hetCyc¹ and E is hetCyc⁴, where hetCyc⁴ is asdefined for General Formula I. In one embodiment, hetCyc⁴ is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N, O and S wherein the S is optionally oxidized to SO₂,and wherein the heterocyclic ring is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros),C1-C6 alkoxy and (C1-C6 alkoxy)C1-C6 alkyl.

In one embodiment, D is hetCyc¹ and E is hetCyc⁴, wherein hetCyc⁴ is a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N, O, and S wherein the S is optionally oxidized to SO₂and wherein the heterocyclic ring is optionally substituted with OH orC1-C6 alkoxy.

In one embodiment, D is hetCyc¹ and E is hetCyc⁴, wherein hetCyc⁴ is a4-6 membered heterocyclic ring having a ring heteroatom selected from Oand S wherein the S is optionally oxidized to SO₂, and wherein theheterocyclic ring is optionally substituted with OH or C1-C6 alkoxy.

Non-limiting examples when D is hetCyc¹ and E is hetCyc⁴ include thestructures:

In one embodiment, D is hetCyc¹ and E is hetCyc⁴C(═O)—, where hetCyc⁴ isas defined for General Formula I. In one embodiment, hetCyc⁴ is (a) a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N, O and S wherein said S is optionally oxidized to SO₂,(b) a 7-8 membered bridged heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, (c) a 6-12 membered fused bicyclicheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O and optionally independently substituted with 1-2 C1-C6alkyl subsitutents, or (d) a 7-10 membered spirocyclic heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereineach of said heterocyclic rings is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros),C1-C6 alkoxy, (C1-C6 alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6alkyl)C(═O)—, a 5-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, and phenyl.

In one embodiment, D is hetCyc¹ and E is hetCyc⁴C(═O)—, where hetCyc⁴ is(a) a 5-6 membered heterocyclic ring, (b) a 7-8 membered bridgedheterocyclic ring, (c) a 6-12 membered fused bicyclic heterocyclic ring,or (d) a 7-10 membered spirocyclic heterocyclic ring, wherein each ofthe heterocyclic rings has 1-2 ring heteroatoms independently selectedfrom N and O, and wherein each of the heterocyclic rings is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, OH, CN, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), C1-C6 alkoxy and (C1-C6 alkoxy)C1-C6alkyl.

In one embodiment, D is hetCyc¹ and E is hetCyc⁴C(═O)—, where hetCyc⁴ is(a) a 4-6 membered heterocyclic ring, (b) a 7-8 membered bridgedheterocyclic ring, (c) a 6-12 membered fused bicyclic heterocyclic ring,or (d) a 7-10 membered spirocyclic heterocyclic ring, wherein each ofthe heterocyclic rings has 1-2 ring heteroatoms independently selectedfrom N and O, and wherein each of the heterocyclic rings is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, OH, CN, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), C1-C6 alkoxy, (C1-C6 alkoxy)C1-C6 alkyl,(C3-C6)cycloalkyl, a 5-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, and phenyl wherein saidphenyl is optionally substituted with one or more substituents selectedfrom halogen, C1-C6 alkyl and C1-C6 alkoxy.

In one embodiment, D is pyrrolidinyl, piperidinyl or piperazinyl, and Eis hetCyc⁴C(═O)—, where hetCyc⁴ is (a) a 5-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinthe ring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, OH, CN,C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy,(C1-C6 alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, a 5-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, and phenyl (b) a 7-8 membered bridged heterocyclic ringhaving a ring nitrogen atom, (c) a 6-12 membered fused bicyclicheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O and optionally substituted with 1-2 groups independentlyselected from C1-C6 alkyl, or (d) a 7-10 membered spirocyclicheterocyclic ring a ring nitrogen atom.

In one embodiment, D is pyrrolidinyl, piperidinyl or piperazinyl, and Eis hetCyc⁴C(═O)—, where hetCyc⁴ is a 5-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinthe ring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, OH, CN,C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy,(C1-C6 alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, a 5-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, and phenyl. In one embodiment, the ring is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, OH, CN, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), C1-C6 alkoxy and (C1-C6 alkoxy)C1-C6alkyl.

Non-limiting examples when D is hetCyc¹ and E is hetCyc⁴C(═O)— includethe structures:

In one embodiment, D is hetCyc¹ and E is hetCyc⁴(C1-C3 alkyl)C(═O)—where hetCyc⁴ is as defined for General Formula I. In one embodiment,hetCyc⁴ is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, and wherein the heterocyclic ringis optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, OH, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy, (C1-C6alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, a 5-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, andphenyl wherein said phenyl is optionally substituted with one or moresubstituents selected from halogen, C1-C6 alkyl and C1-C6 alkoxy. In oneembodiment, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros),C1-C6 alkoxy, (C1-C6 alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, a 5-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, and phenyl.

In one embodiment, D is hetCyc¹ and E is hetCyc⁴(C1-C3 alkyl)C(═O)—,where hetCyc⁴ is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein theheterocyclic ring is unsubstituted or substituted with C1-C6 alkyl. Inone embodiment, D is hetCyc¹ and E is hetCyc⁴(C1-C3 alkyl)C(═O)—, wherehetCyc⁴ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein the heterocyclic ring isunsubstituted.

In one embodiment, D is piperazinyl and E is hetCyc⁴(C1-C3 alkyl)C(═O)—,where hetCyc⁴ is a 5-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein theheterocyclic ring is unsubstituted or substituted with C1-C6 alkyl. Inone embodiment, the ring is unsubstituted.

Non-limiting examples when D is hetCyc¹ and E is hetCyc⁴(C1-C3alkyl)C(═O)— include the structures:

In one embodiment, D is hetCyc¹ and E is (hetCyc⁴)C(═O)C1-C2 alkyl,where hetCyc⁴ is as defined for General Formula I. In one embodiment,hetCyc⁴ is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, and wherein the heterocyclic ringis optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, OH, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy, (C1-C6alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, a 5-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, andphenyl wherein said phenyl is optionally substituted with one or moresubstituents selected from halogen, C1-C6 alkyl and C1-C6 alkoxy. In oneembodiment, the heterocyclic ring is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros),C1-C6 alkoxy and (C1-C6 alkoxy)C1-C6 alkyl.

In one embodiment, D is hetCyc¹ and E is (hetCyc⁴)C(═O)C1-C2 alkyl,where hetCyc⁴ is a 4-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein theheterocyclic ring is unsubstituted. In one embodiment, D is piperazinyland hetCyc⁴ is a 4-6 membered heterocyclic ring having a ring nitrogenatom. In one embodiment, hetCyc⁴ is 5-6 membered heterocyclic ringhaving a ring nitrogen atom.

A non-limiting example when D is hetCyc¹ and E is (hetCyc⁴)C(═O)C1-C2alkyl is the structure:

In one embodiment, D is hetCyc¹ and E is hetCyc⁴C(═O)NH—, where hetCyc⁴is as defined for General Formula I. In one embodiment, hetCyc⁴ is (a) a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein said ring is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, OH, CN, C1-C6 alkyl (optionally substituted with1-3 fluoros), C1-C6 alkoxy, and (C1-C6 alkoxy)C1-C6 alkyl, (b) a 7-8membered bridged heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, (c) a 8-12 membered fused bicyclicheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, or (d) a 7-10 membered spirocyclic heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O.

Non-limiting examples when D is hetCyc¹ and E is hetCyc⁴C(═O)NH— includethe structures:

In one embodiment, D is hetCyc¹ and E is Ar²; Ar²C(═O)—; Ar²C1-C6 alkyl;(Ar²)hydroxy C2-C6 alkyl; or Ar²(C1-C3 alkyl)C(═O)— wherein the alkylportion is optionally substituted with one or two groups independentlyselected from the group consisting of OH, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N— where R^(e) and R^(f) are independently H or C1-C6 alkyl,or R^(e) and R^(f) together with the nitrogen to which they are attachedform a 5-6 membered azacyclic ring optionally having an additional ringheteroatom selected from N and O; wherein for each instance of E, Ar² isphenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C6alkyl, C1-C6 alkoxy (optionally substituted with 1-3 fluoros),fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, CN, a 5-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, and R^(i)R^(j)N— where R^(i) and R^(j) areindependently H and C1-C6 alkyl. In one embodiment, Ar² is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen and C1-C3 alkyl.

In one embodiment, D is hetCyc¹ and E is Ar²; Ar²C(═O)—; Ar²C1-C6 alkyl;(Ar²)hydroxy C2-C6 alkyl; or Ar²(C1-C3 alkyl)C(═O)— wherein the alkylportion is optionally substituted with one or two groups independentlyselected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6alkyl, C1-C6 alkoxy and R^(e)R^(f)N— where R^(e) and R^(f) areindependently H or C1-C6 alkyl; wherein for each instance of E, Ar² isphenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C3alkyl, C1-C3 alkoxy, fluoroC1-C3 alkyl, difluoroC1-C3 alkyl andtrifluoroC1-C3 alkyl. In one embodiment, Ar² is phenyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen and C1-C3 alkyl.

In one embodiment, D is hetCyc¹ and E is Ar² wherein Ar² is as definedfor General Formula I. In one embodiment, Ar² is phenyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen. In one embodiment, hetCyc¹ ispyrrolidinyl, piperidinyl or morpholinyl. Non-limiting examples when Dis hetCyc¹ and E is Ar² include the structures:

In one embodiment, D is hetCyc¹ and E is Ar²C(═O)— wherein Ar² is asdefined for General Formula I. In one embodiment, Ar² is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen or a 5-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O. In one embodiment, hetCyc¹ is piperazinyl. Non-limitingexamples include the structures:

In one embodiment, D is hetCyc¹ and E is Ar²C1-C6 alkyl wherein Ar² isas defined for General Formula I. In one embodiment, Ar² is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C3 alkyl, C1-C3alkoxy, CN, and R^(i)R^(j)N— where R^(i) and R^(j) are independently Hand C1-C6 alkyl. In one embodiment, hetCyc¹ is piperazinyl, piperidinyl,azetidinyl, or piperazin-2-onyl. In one embodiment, E is Ar²C1-C2 alkylwhere Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C6alkyl, C1-C6 alkoxy, CN, and R^(i)R^(j)N— where R^(i) and R^(j) areindependently H and C1-C6 alkyl.

Non-limiting examples when D is hetCyc¹ and E is Ar²C1-C6 alkyl includethe structures:

In one embodiment, D is hetCyc¹ and E is (Ar²)hydroxy C2-C6 alkylwherein Ar² is as defined for General Formula I. In one embodiment, Ar²is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen. In oneembodiment, hetCyc¹ is piperazinyl.

Non-limiting examples when D is hetCyc¹ and E is (Ar²)hydroxy C2-C6alkyl include the structures:

In one embodiment, D is hetCyc¹ and E is Ar²(C1-C3 alkyl)C(═O)—, whereinAr² is as defined for General Formula I and the alkyl portion isoptionally substituted with one or two groups independently selectedfrom the group consisting of OH, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), hydroxyC1-C6 alkyl, C1-C6 alkoxy and R^(e)R^(f)N—,where R^(e) and R^(f) are independently H and C1-C6 alkyl, or R^(e) andR^(f) together with the nitrogen to which they are attached form a 5-6membered azacyclic ring optionally having an additional ring heteroatomselected from N and O. In one embodiment, hetCyc¹ is piperazinyl. In oneembodiment, Ar² is phenyl optionally substituted with one or moresubstituents independently selected from halogen, CN, C1-C6 alkyl andC1-C6 alkoxy (optionally substituted with 1-3 fluoros).

In one embodiment, D is hetCyc¹ and E is Ar²(C1-C3 alkyl)C(═O)—, whereinAr² is as defined for General Formula I and the alkyl portion isoptionally substituted with one or two groups independently selectedfrom the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) are independently H andC1-C6 alkyl. In one embodiment, hetCyc¹ is piperazinyl.

Non-limiting examples when D is hetCyc¹ and E is Ar²(C1-C3 alkyl)C(═O)—include the structures:

In one embodiment, D is hetCyc¹ and E is hetAr²C(═O)—;(hetAr²)hydroxyC2-C6 alkyl; or hetAr²(C1-C3 alkyl)C(═O)— wherein thealkyl portion is optionally substituted with one or two groupsindependently selected from the group consisting of OH, C1-C6 alkyl,hydroxyC1-C6 alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f)are independently H or C1-C6 alkyl, or R^(e) and R^(f) together with thenitrogen to which they are attached form a 5-6 membered azacyclic ringoptionally having an additional ring heteroatom selected from N and O;wherein for each instance of E, hetAr² is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N, O and S andoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy(optionally substituted with 1-3 fluoros), fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, hydroxyC1-C6 alkyl,(C3-C6)cycloalkyl, (C1-C6 alkoxy)C1-C6 alkyl, CN, and R′R″N— where R′and R″ are independently H or C1-C6 alkyl.

In one embodiment, D is hetCyc¹ and E is hetAr²C(═O)—;(hetAr²)hydroxyC2-C6 alkyl; hetAr²(C1-C3 alkyl)C(═O)— wherein the alkylportion is optionally substituted with one or two groups independentlyselected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) areindependently H or C1-C6 alkyl; or hetAr²C1-C6 alkyl; wherein for eachinstance of E, hetAr² is a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N and O and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy (optionallysubstituted with 1-3 fluoros), fluoroC1-C3 alkyl, difluoroC1-C3 alkyl,trifluoroC1-C3 alkyl and hydroxyC1-C3 alkyl.

In one embodiment, hetAr² is pyridyl, pyridazinyl, imidazolyl, pyrazolylor isoxazolyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C3alkyl, C1-C3 alkoxy (optionally substituted with 1-3 fluoros),fluoroC1-C3 alkyl, difluoroC1-C3 alkyl, trifluoroC1-C3 alkyl,hydroxyC1-C6 alkyl, (C3-C6)cycloalkyl and (C1-C6 alkoxy)C1-C6 alkyl. Inone embodiment, hetAr² is optionally substituted with one or moresubstituents independently selected C1-C3 alkyl.

In one embodiment, D is hetCyc¹ and E is hetAr²C(═O)—, where hetAr² isas defined for General Formula I. In one embodiment, hetAr² is a 5-6membered heteroaryl ring having 1-2 ring heteroatoms independentlyselected from N and O and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C1-C3 alkyl, (C3-C6)cycloalkyl and (C1-C6 alkoxy)C1-C6 alkyl.In one embodiment, hetCyc¹ is piperazinyl.

Non-limiting examples when D is hetCyc¹ and E is hetAr²C(═O)— includethe structures:

In one embodiment, D is hetCyc¹ and E is (hetAr²)hydroxyC2-C6 alkylwhere hetAr² is as defined for General Formula I. In one embodiment,hetAr² is a 5-6 membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O wherein said ring is unsubstituted.In one embodiment, hetAr² is pyridinyl. Non-limiting examples includesthe structures:

In one embodiment, D is hetCyc¹ and E is hetAr²(C1-C3 alkyl)C(═O)—,wherein hetAr² is as defined for General Formula I and the alkyl portionis optionally substituted with one or two groups independently selectedfrom the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6alkoxy (optionally substituted with 1-3 fluoros) and R^(e)R^(f)N—, whereR^(e) and R^(f) are independently H or C1-C6 alkyl. In one embodiment,the alkyl portion of hetAr²(C1-C3 alkyl)C(═O)— is unsubstituted. In oneembodiment, hetAr² is a 5-6 membered heteroaryl ring having 1-2 ringnitrogen atoms and optionally substituted with one or more substituentsindependently selected from the group consisting of halogen and C1-C6alkyl. In one embodiment, hetCyc¹ is piperazinyl.

Non-limiting examples D is hetCyc¹ and E is hetAr²(C1-C3 alkyl)C(═O)—include the structures:

In one embodiment, D is hetCyc¹ and E is R¹R²NC(═O)—; R¹R²N(C1-C3alkyl)C(═O)— wherein the alkyl portion is optionally substituted withphenyl; R¹R²NC(═O)C1-C2 alkyl; or R¹R²NC(═O)NH—; where in each instance,R¹ is H, C1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl, and R² is H, C1-C6alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6alkyl (optionally substituted with 1-3 fluoros), Cyc³, hydroxyC1-C6alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O), hetCyc⁷,Ar³, Ar³C1-C3 alkyl-, hydroxyC1-C6 alkoxy or (3-6C cycloalkyl)CH₂O—.

In one embodiment, D is hetCyc¹ and E is R¹R²NC(═O)—; R¹R²N(C1-C3alkyl)C(═O)— wherein the alkyl portion is optionally substituted withphenyl; R¹R²NC(═O)C1-C2 alkyl; or R¹R²NC(═O)NH—; where in each instance,R¹ is H or C1-C6 alkyl, and R² is H, C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl (optionally substitutedwith 1-3 fluoros), Cyc³, hydroxyC1-C6 alkyl (optionally substituted with1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros),(C1-C6 alkoxy)C(═O), hetCyc⁷, Ar³ or Ar³C1-C3 alkyl-.

In one embodiment, D is hetCyc¹ and E is R¹R²NC(═O)—, where R¹ is H,C1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl, and R² is C1-C6 alkyl(optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl(optionally substituted with 1-3 fluoros), Cyc³, hydroxyC1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(═O), hetCyc⁷, Ar³,Ar³C1-C3 alkyl-, hydroxyC1-C6 alkoxy or (3-6C cycloalkyl)CH₂O—. In oneembodiment, hetCyc¹ is pyrrolidinyl, piperidinyl (optionally substitutedwith C1-C3 alkyl), piperazinyl, morpholinyl or azetidinyl. In oneembodiment, hetCyc¹ is pyrrolidinyl, piperidinyl (optionally substitutedwith C1-C3 alkyl), piperazinyl, or morpholinyl.

Non-limiting examples when D is hetCyc¹ and E is R¹R²NC(═O)— include thestructures:

In one embodiment, D is hetCyc¹ and E is R¹R²N(C1-C3 alkyl)C(═O)—wherein the C1-C3 alkyl portion is optionally substituted with phenyl.In one embodiment, R¹ is H or C1-C6 alkyl and R² is H, C1-C6 alkyl(optionally substituted with 1-3 fluoros) or (C1-C6 alkoxy)C(═O)—.Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is R¹R²NC(═O)C1-C2 alkyl. In oneembodiment, R¹ is H or C1-C6 alkyl and R² is C1-C6 alkyl (optionallysubstituted with 1-3 fluoros). Non-limiting examples include thestructures:

In one embodiment, D is hetCyc¹ and E is R¹R²NC(═O)NH—, where R¹ is H orC1-C6 alkyl, and R² is C1-C6 alkyl (optionally substituted with 1-3fluoros). Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is CH₃SO₂(C1-C6 alkyl)C(═O)—. Anon-limiting example is the structure:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkyl)SO₂—. Non-limitingexamples include the structures:

In one embodiment, D is hetCyc¹ and E is (C3-C6 cycloalkyl)CH₂SO₂—. Anon-limiting example is the structure:

In one embodiment, D is hetCyc¹ and E is hetCyc¹-SO₂—, where hetCyc⁵ isa 5-6 membered heterocyclic ring having a ring heteroatom selected fromO and N. Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is R⁴R⁵NSO₂—, where R⁴ and R⁵ areindependently H or C1-C6 alkyl. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc¹ and E is R⁶C(═O)NH—, where R⁶ is C1-C6alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkoxy)(C1-C6 alkyl),phenyl or hetCyc⁸. Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is hetCyc⁶, where hetCyc⁶ is a 5membered heterocyclic ring having one or two ring heteroatomsindependently selected from N and O, wherein the ring substituted withoxo and wherein the ring is further optionally substituted with one ormore substituents independently selected from the group consisting of OHand C1-6 alkyl. Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is hetAr²C1-C6 alkyl, where hetAr²is as defined for General Formula I. In one embodiment, D is hetCyc¹ andE is hetAr²C1-C6 alkyl, where hetAr² is a 5-6 membered heteroaryl ringhaving 1-3 ring heteroatoms independently selected from N and O, andoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl,trifluoroC1-C6 alkyl, C1-C6 alkoxy (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl, CN and (R^(a)R^(b)N)C1-C6 alkyl; andhetCyc¹ is piperazinyl (optionally substituted with oxo), piperidinyl orpyrrolidinyl. In one embodiment, hetAr² is a 5-6-membered heteroarylring having 1-2 ring nitrogen atoms optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, C1-C6 alkyl, trifluoroC1-C6 alkyl, C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl, CN and(R^(a)R^(b)N)C1-C6 alkyl. In one embodiment, hetAr² is pyridyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl,trifluoroC1-C6 alkyl, C1-C6 alkoxy (optionally substituted with 1-3fluoros), hydroxyC1-C6 alkyl, CN and (R^(a)R^(b)N)C1-C6 alkyl. In oneembodiment, hetAr² is pyridyl optionally substituted with C1-C6 alkoxy(optionally substituted with 1-3 fluoros). In one embodiment, hetAr² isa 5-membered heteroaryl ring having 1-2 ring nitrogen atoms optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C1-C6 alkyl, trifluoroC1-C6 alkyl,C1-C6 alkoxy (optionally substituted with 1-3 fluoros), hydroxyC1-C6alkyl, CN and (R^(a)R^(b)N)C1-C6 alkyl.

Non-limiting examples when D is hetCyc¹ and E is hetAr²C1-C6 alkylinclude the structures:

In one embodiment, D is hetCyc¹ and E is (hetCyc⁴)C1-C6 alkyl, wherehetCyc⁴ is as defined for General Formula I. In one embodiment, E is(hetCyc⁴)C1-C6 alkyl, where hetCyc⁴ is a 4-6 membered heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O, whereinsaid heterocyclic ring is optionally substituted with (C1-C6alkyl)C(═O)—. In one embodiment, D is hetCyc¹ and E is hetCyc⁴(C1-C2alkyl), where hetCyc⁴ is a 4-6 membered heterocyclic ring having 1-2ring heteroatoms independently selected from N and O, wherein saidheterocyclic ring is optionally substituted with (C1-C6 alkyl)C(═O)—.

Non-limiting embodiments when D is hetCyc¹ and E is (hetCyc⁴)C1-C6 alkylinclude the structures:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkoxy)C1-C6 alkylwherein said alkoxy portion is optionally substituted with 1-3 fluoros.Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is (C3-C6 cycloalkoxy)C1-C6 alkyl.A non-limiting example is the structure:

In one embodiment, D is hetCyc¹ and E is (C3-C6 cycloalkyl)C1-C6 alkylwherein said cycloalkyl is optionally substituted with 1-2 fluoros.Non-limiting examples include the structures:

In one embodiment, D is hetCyc¹ and E is (R^(g)R^(h)N)C1-C6 alkylwherein R^(g) and R^(h) are independently H or C1-C6 alkyl. Non-limitingexamples include the structures:

In one embodiment, D is hetCyc¹ and E is Ar²—O—, where Ar² is as definedfor General Formula I. In one embodiment, Ar² is phenyl optionallysubstituted with one or more halogens. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkylSO₂)C1-C6 alkyl. Anon-limiting example is the structure:

In one embodiment, D is hetCyc¹ and E is (C1-C6 alkoxy)C(═O)NHC1-C6alkyl. A non-limiting example is the structure:

In one embodiment, D is hetCyc¹ and E is (C3-C6 cycloalkyl)SO₂— whereinsaid cycloalkyl is optionally substituted with C1-C6 alkyl. Anon-limiting example includes the structure:

In one embodiment, D is hetCyc¹ and E is (N—(C1-C3alkyl)pyridinonyl)C1-C3 alkyl. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc¹ and E is (Ar⁴SO₂)C1-C6 alkyl where Ar⁴is as defined for Formula I. In one embodiment, Ar⁴ is unsubstitutedphenyl. A non-limiting example when D is hetCyc¹ and E is (Ar⁴SO₂)C1-C6alkyl includes the structure:

In one embodiment, D is hetCyc¹ and E is (N—(C1-C3alkyl)pyridinonyl)C1-C3 alkyl. Non-limiting examples include thestructures:

In one embodiment of the D-E group, D is hetCyc¹ (wherein hetCyc¹ is a4-6 membered heterocyclic ring having 2 ring atoms and is optionallysubstituted with a C3-C6 cycloalkylidene ring, or an oxo group) and theE group is on a ring nitrogen atom of the D ring, wherein E is selectedfrom (a) hydrogen, (d) C1-C6 alkyl optionally substituted with one tothree fluoros, (e) hydroxyC1-C6 alkyl optionally substituted with one tothree fluoros, (h) (C1-C6 alkoxy)hydroxy C1-C6 alkyl optionallysubstituted with one to three fluoros, (i) (C1-C6 alkyl)C(═O)—optionally substituted with one to three fluoros, (j) (hydroxy C1-C6alkyl)C(═O)— optionally substituted with one to three fluoros, (k)(C1-C6 alkoxy)C(═O)—, (1) (C1-C6 alkoxy)(C1-C6 alkyl)C(═O)—, (n) Cyc¹,(o) Cyc¹C(═O)—, (p) Cyc¹(C1-C6 alkyl)C(═O)— wherein the alkyl portion isoptionally substituted with one or more groups independently selectedfrom the group consisting of OH, fluoro, C1-C3 alkoxy and R^(c)R^(d)N—,where R^(c) and R^(d) are independently H or C1-C6 alkyl, (q) hetCyc⁴,(r) hetCyc⁴C(═O)—, (s) hetCyc⁴(C1-C3 alkyl)C(═O)—, (t)(hetCyc⁴)C(═O)C1-C2 alkyl, (w) Ar²C(═O)—, (x) Ar²C1-C6 alkyl, (y)(Ar²)hydroxy C2-C6 alkyl, (z) Ar²(C1-C3 alkyl)C(═O)— wherein the alkylportion is optionally substituted with one or two groups independentlyselected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) areindependently H or C1-C6 alkyl, (aa) hetAr²C(═O)—, (bb)(hetAr²)hydroxyC2-C6 alkyl, (cc) hetAr²(C1-C3 alkyl)C(═O)— wherein thealkyl portion is optionally substituted with one or two groupsindependently selected from the group consisting of OH, C1-C6 alkyl,hydroxyC1-C6 alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f)are independently H or C1-C6 alkyl, (dd) R¹R²NC(═O)—, (ee) R¹R²N(C1-C3alkyl)C(═O)— wherein the alkyl portion is optionally substituted withphenyl, (ff) R¹R²NC(═O)C1-C2 alkyl, (hh) CH₃SO₂(C1-C6 alkyl)C(═O)—, (ii)(C1-C6 alkyl)SO₂—, (jj) (C3-C6 cycloalkyl)CH₂SO₂—, (kk) hetCyc⁵-SO₂—,(ll) R⁴R⁵NSO₂—, (nn) hetCyc⁶, (oo) hetAr²C1-C6 alkyl, (pp)(hetCyc⁴)C1-C6 alkyl, (qq) (C1-C6 alkoxy)C1-C6 alkyl wherein said alkoxyportion is optionally substituted with 1-3 fluoros, (rr) (C3-C6cycloalkoxy)C1-C6 alkyl, (ss) (C3-C6 cycloalkyl)C1-C6 alkyl wherein saidcycloalkyl is optionally substituted with 1-2 fluoros, (tt)(R^(g)R^(h)N)C1-C6 alkyl wherein R^(g) and R^(h) are independently H orC1-C6 alkyl, (vv) (C1-C6 alkylSO₂)C1-C6 alkyl, (ww) (C1-C6alkoxy)C(═O)NHC1-C6 alkyl, (C3-C6 cycloalkyl)SO₂— wherein saidcycloalkyl is optionally substituted with C1-C6 alkyl, (yy) (C3-C6cycloalkyl)SO₂— wherein said cycloalkyl is optionally substituted withC1-C6 alkyl, (aaa) (N—(C1-C3 alkyl)pyridinonyl)C1-C3 alkyl, or (bbb)(Ar⁴SO₂)C1-C6 alkyl. In one embodiment, D is a piperazinyl ring.

In one embodiment of the D-E group, D is piperidinyl, pyrrolidinyl,azetidinyl or morphylinyl, each of which is optionally substituted withC1-C3 alkyl, fluoroC1-C3 alkyl, difluoroC1-C3 alkyl, or trifluoroC1-C3alkyl, wherein E is selected from (a) hydrogen, (b) OH, (c)R^(a)R^(b)N—, (f) C1-C6 alkoxy optionally substituted with one to threefluoros, (g) hydroxy(C1-C6 alkoxy) optionally substituted with one tothree fluoros, (i) (C1-C6 alkyl)C(═O)— optionally substituted with oneto three fluoros, (k) (C1-C6 alkoxy)C(═O)—, (m) HC(═O)—, (r)hetCyc⁴C(═O)—, (u) hetCyc⁴C(═O)NH—, (v) Ar², (dd) R¹R²NC(═O)—, (x)Ar²C1-C6 alkyl, (ff) R¹R²NC(═O)C1-C2 alkyl, (gg) R¹R²NC(═O)NH—, (ii)(C1-C6 alkyl)SO₂—, (11) R⁴R⁵NSO₂—, (mm) R⁶C(═O)NH—, (nn) hetCyc⁶, or(uu) Ar²—O—. In one embodiment, D is a piperidinyl ring.

In one embodiment of Formula I, D is hetCyc², where hetCyc² is a 7-8membered bridged heterocyclic ring having 1-3 ring heteroatomsindependently selected from N and O, wherein the heterocyclic ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of C1-C3 alkyl. In one embodiment,hetCyc² is a 7-8 membered bridged heterocyclic ring having 1-2 ringnitrogen atoms, wherein the ring is optionally substituted with one ormore substituents independently selected from the group consisting ofC1-C3 alkyl. In one embodiment, hetCyc² is unsubstituted. Non-limitingexamples of D when represented by hetCyc² include the structures:

where the asterisk indicates the point of attachment to the E group.

In one embodiment of Formula I, D is hetCyc² and E is (a) hydrogen, (b)OH, (c) R^(a)R^(b)N— where R^(a) is H or C1-C6 alkyl and R^(b) is H,C1-C6 alkyl or phenyl, (d) C1-C6 alkyl optionally substituted with oneto three fluoros, (e) hydroxyC1-C6 alkyl optionally substituted with oneto three fluoros, (f) C1-C6 alkoxy optionally substituted with one tothree fluoros, (i) (C1-C6 alkyl)C(═O)— optionally substituted with oneto three fluoros, (k) (C1-C6 alkoxy)C(═O)— (o) Cyc¹C(═O)—, (w)Ar²C(═O)—, (x) Ar²C1-C6 alkyl, (y) (Ar²)hydroxy C2-C6 alkyl, (aa)hetAr²C(═O)—, (cc) hetAr²(C1-C3 alkyl)C(═O)— wherein the alkyl portionis optionally substituted with one or two groups independently selectedfrom the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) are independently H orC1-C6 alkyl, or R^(e) and R^(f) together with the nitrogen to which theyare attached form a 5-6 membered azacyclic ring optionally having anadditional ring heteroatom selected from N and O, (ee) R¹R²N(C1-C3alkyl)C(═O)— wherein said alkyl portion is optionally substituted withphenyl, (oo) hetAr²C1-C6 alkyl or (qq) (C1-C6 alkoxy)C1-C6 alkyl whereinsaid alkoxy portion is optionally substituted with 1-3 fluoros.

In one embodiment, D is hetCyc² and E is hydrogen. Non-limiting examplesinclude the structures:

In one embodiment, D is hetCyc² and E is OH. A non-limiting example isthe structure:

In one embodiment, D is hetCyc² and E is R^(a)R^(b)N— where R^(a) is Hor C1-C6 alkyl and R^(b) is H, C1-C6 alkyl or phenyl. In one embodiment,D is hetCyc² and E is R^(a)R^(b)N— where R^(a) and R^(b) are H. Anon-limiting example is the structure:

In one embodiment, D is hetCyc² and E is C1-C6 alkyl optionallysubstituted with one to three fluoros. A non-limiting example includesthe structure:

In one embodiment, D is hetCyc² and E is C1-C6 alkoxy optionallysubstituted with one to three fluoros. A non-limiting example is thestructure:

In one embodiment, D is hetCyc² and E is (C1-C6 alkyl)C(═O)— optionallysubstituted with one to three fluoros. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc² and E is (C1-C6 alkoxy)C(═O)—.Non-limiting examples include the structures:

In one embodiment, D is hetCyc² and E is Ar²C(═O)—, where Ar² is asdefined for General Formula I. In one embodiment, Ar² is phenyloptionally substituted with one or more substituents independentlyselected from halogen and C1-C6 alkoxy (optionally substituted with 1-3fluoros). Non-limiting examples when D is hetCyc² and E is Ar²C(═O)include the structures:

In one embodiment, D is hetCyc² and E is Ar²C1-C6 alkyl where Ar² is asdefined for General Formula I. In one embodiment, Ar² is anunsubstituted phenyl. Non-limiting examples when D is hetCyc² and E isAr²C1-C6 alkyl include the structures:

In one embodiment, D is hetCyc² and E is hetAr²C(═O)— where hetAr² is asdefined for Formula I. In one embodiment hetAr² is a 6-memberedheteroaryl ring having 1-2 ring nitrogen atoms and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy (optionallysubstituted with 1-3 fluoros), fluoroC1-C6 alkyl, difluoroC1-C6 alkyl,trifluoroC1-C6 alkyl, hydroxyC1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6alkoxy)C1-C6 alkyl, CN and R′R″N— where R′ and R″ are independently H orC1-C3 alkyl. In one embodiment hetAr² is pyridyl optionally substitutedwith one or more substituents independently selected from halogen andC1-C6 alkoxy (optionally substituted with 1-3 fluoros). Non-limitingexamples when D is hetCyc² and E is hetAr²C(═O)— include the structures:

In one embodiment, D is hetCyc² and E is hetAr²(C1-C3 alkyl)C(═O)—wherein the alkyl portion is optionally substituted with one or twogroups independently selected from the group consisting of OH, C1-C6alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e)and R^(f) are independently H or C1-C6 alkyl, or R^(e) and R^(f)together with the nitrogen to which they are attached form a 5-6membered azacyclic ring optionally having an additional ring heteroatomselected from N and O, and hetAr² is as defined for Formula I. In oneembodiment, E is hetAr²(C1-C3 alkyl)C(═O)— wherein the alkyl portion isunsubstituted. In one embodiment, hetAr² is is a 6-membered heteroarylring having 1-2 ring nitrogen atoms and optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, C1-C6 alkyl, C1-C6 alkoxy (optionally substituted with 1-3fluoros), fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl,hydroxyC1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6 alkoxy)C1-C6 alkyl, CN andR′R″N— where R′ and R″ are independently H or C1-C3 alkyl. In oneembodiment hetAr² is pyridyl optionally substituted with one or moresubstituents independently selected from halogen. A non-limiting exampleD is hetCyc² and E is hetAr²(C1-C3 alkyl)C(═O)— includes the structure:

In one embodiment, D is hetCyc² and E is R¹R²N(C1-C3 alkyl)C(═O)—. Anon-limiting example is the structure:

In one embodiment, D is hetCyc² and E is hetAr²C1-C6 alkyl, where hetAr²is as defined for Formula I. In one embodiment, E is hetAr²C1-C6 alkylwherein the alkyl portion is unsubstituted. In one embodiment, hetAr² isa 6-membered heteroaryl ring having 1-2 ring nitrogen atoms andoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy(optionally substituted with 1-3 fluoros), fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, hydroxyC1-C6 alkyl,(C3-C6)cycloalkyl, (C1-C6 alkoxy)C1-C6 alkyl, CN and R′R″N— where R′ andR″ are independently H or C1-C3 alkyl. In one embodiment hetAr² ispyridyl optionally substituted with C1-C6 alkoxy (optionally substitutedwith 1-3 fluoros). Non-limiting examples when D is hetCyc² and E ishetAr²C1-C6 alkyl include the structures:

In one embodiment, D is hetCyc² and E is (C1-C6 alkoxy)C1-C6 alkylwherein said alkoxy portion is optionally substituted with 1-3 fluoros.A non-limiting example includes the structure:

In one embodiment, D is hetCyc² (where hetCyc² is a 7-8 membered bridgedheterocyclic ring having two ring nitrogen atoms, wherein theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C3alkyl), and E is on a ring nitrogen atom of hetCyc² wherein E is (a)hydrogen, (d) C1-C6 alkyl optionally substituted with one to threefluoros, (i) (C1-C6 alkyl)C(═O)— optionally substituted with one tothree fluoros, (w) Ar²C(═O)—, (x) Ar²C1-C6 alkyl, (aa) hetAr²C(═O)—,(oo) hetAr²C1-C6 alkyl, or (qq) (C1-C6 alkoxy)C1-C6 alkyl wherein saidalkoxy portion is optionally substituted with 1-3 fluoros.

In one embodiment, D is hetCyc² (where hetCyc² is a 7-8 membered bridgedheterocyclic ring having one ring nitrogen atom, wherein theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C3alkyl), and E is on a ring carbon atom of hetCyc² wherein E is (b) OH,(c) R^(a)R^(b)N— where R^(a) is H or C1-C6 alkyl and R^(b) is H, C1-C6alkyl or phenyl, or (f) C1-C6 alkoxy optionally substituted with one tothree fluoros.

In one embodiment of Formula I, D is hetCyc³, where hetCyc³ is a 7-11membered heterospirocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and wherein the ring is optionallysubstituted with C1-C3 alkyl. In one embodiment, hetCyc³ isunsubstituted. Non-limiting examples when D is represented by hetCyc³include the structures:

where the asterisk indicates the point of attachment to the E group.

In one embodiment, D is hetCyc³ and E is selected from (a) hydrogen, (c)R^(a)R^(b)N— where R^(a) is H or C1-C6 alkyl and R^(b) is H, C1-C6 alkylor phenyl, (d) C1-C6 alkyl optionally substituted with one to threefluoros, (e) hydroxyC1-C6 alkyl optionally substituted with one to threefluoros, (i) (C1-C6 alkyl)C(═O)— optionally substituted with one tothree fluoros, (j) (hydroxy C1-C6 alkyl)C(═O)— optionally substitutedwith one to three fluoros, (k) (C1-C6 alkoxy)C(═O)—, (o) Cyc¹C(═O)—, (p)Cyc¹(C1-C6 alkyl)C(═O), (r) hetCyc⁴C(═O)—, (w) Ar²C(═O)—, (x) Ar²C1-C6alkyl, (y) (Ar²)hydroxy C2-C6 alkyl, (z) Ar²(C1-C3 alkyl)C(═O)— whereinsaid alkyl portion is optionally substituted with one or two groupsindependently selected from the group consisting of OH, C1-C6 alkyl(optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl, C1-C6alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) are independently H orC1-C6 alkyl, or R^(e) and R^(f) together with the nitrogen to which theyare attached form a 5-6 membered azacyclic ring optionally having anadditional ring heteroatom selected from N and O, (dd) R¹R²NC(═O), (ee)R¹R²N(C1-C3 alkyl)C(═O)—, (mm) R⁶C(═O)NH—, (xx) (C3-C6cycloalkoxy)C(═O)— and (zz) Ar⁴CH₂OC(═O)—.

In one embodiment, D is hetCyc³ (wherein a 7-11 memberedheterospirocyclic ring having two ring nitrogen atoms), wherein the ringis optionally substituted with C1-C3 alkyl), and E is on a ring nitrogenatom of ring D, and E is selected from (a) hydrogen, (d) C1-C6 alkyloptionally substituted with one to three fluoros, (e) hydroxyC1-C6 alkyloptionally substituted with one to three fluoros, (i) (C1-C6alkyl)C(═O)— optionally substituted with one to three fluoros, (j)(hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros, (k) (C1-C6 alkoxy)C(═O)—, (o) Cyc¹C(═O)—, (p) Cyc¹(C1-C6alkyl)C(═O), (r) hetCyc⁴C(═O)—, (w) Ar²C(═O)—, (x) Ar²C1-C6 alkyl, (y)(Ar²)hydroxy C2-C6 alkyl, (z) Ar²(C1-C3 alkyl)C(═O)— wherein said alkylportion is optionally substituted with one or two groups independentlyselected from the group consisting of OH, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N—, where R^(e) and R^(f) are independently H or C1-C6 alkyl,or R^(e) and R^(f) together with the nitrogen to which they are attachedform a 5-6 membered azacyclic ring optionally having an additional ringheteroatom selected from N and O, (dd) R¹R²NC(═O), (ee) R¹R²N(C1-C3alkyl)C(═O)—, (xx) (C3-C6 cycloalkoxy)C(═O)— and (zz) Ar⁴CH₂OC(═O)—.

In one embodiment, D is hetCyc³ (wherein hetCyc³ is a 7-11 memberedheterospirocyclic ring having one ring nitrogen atom, wherein the ringis optionally substituted with C1-C3 alkyl), and E is on a ring carbonatom of ring D, and E is selected from (a) hydrogen, (c) R^(a)R^(b)N—where R^(a) is H or C1-C6 alkyl and R^(b) is H, C1-C6 alkyl or phenyl,and (mm) R⁶C(═O)NH—.

In one embodiment, D is hetCyc³ and E is hydrogen. Non-limiting examplesinclude the structures:

In one embodiment, D is hetCyc³ and E is R^(a)R^(b)N— where R^(a) is Hor C1-C6 alkyl and R^(b) is H, C1-C6 alkyl or phenyl. In one embodiment,R^(a) and R^(b) are H. A non-limiting example is the structure:

In one embodiment, D is hetCyc³ and E is C1-C6 alkyl optionallysubstituted with one to three fluoros. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc³ and E is hydroxyC1-C6 alkyl optionallysubstituted with one to three fluoros. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc³ and E is (C1-C6 alkyl)C(═O)— optionallysubstituted with one to three fluoros. Non-limiting examples include thestructures:

In one embodiment, D is hetCyc³ and E is (hydroxy C1-C6 alkyl)C(═O)—optionally substituted with one to three fluoros. Non-limiting examplesinclude the structures:

In one embodiment, D is hetCyc³ and E is (C1-C6 alkoxy)C(═O)—.Non-limiting examples include the structures:

In one embodiment, D is hetCyc³ and E is Cyc¹C(═O)—, where Cyc¹ is asdefined for General Formula I. In one embodiment, Cyc¹ is unsubstituted.Non-limiting examples include the structures:

In one embodiment, D is hetCyc³ and E is Cyc¹(C1-C6 alkyl)C(═O)— whereinsaid alkyl portion is optionally substituted with one or more groupsindependently selected from the group consisting of OH, fluoro, C1-C3alkoxy and R^(c)R^(d)N—, where R^(c) and R^(d) are independently H orC1-C6 alkyl, and Cyc¹ is as defined for General Formula I.

In one embodiment, D is hetCyc³ and E is Cyc¹(C1-C6 alkyl)C(═O)— whereinsaid alkyl portion is unsubstituted, and Cyc¹ is as defined for GeneralFormula I. In one embodiment, Cyc¹ is an unsubstituted C3-C6 cycloalkyl.

Non-limiting examples when D is hetCyc³ and E is Cyc¹(C1-C6 alkyl)C(═O)—include the structures:

In one embodiment, D is hetCyc³ and E is hetCyc⁴C(═O)—, where hetCyc⁴ isas defined for General Formula I. In one embodiment, hetCyc⁴ is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein said ring is unsubstituted. Anon-limiting example when D is hetCyc³ and E is hetCyc⁴C(═O)— is thestructure:

In one embodiment, D is hetCyc³ and E is Ar²C(═O)— where Ar² is asdefined for General Formula I. In one embodiment, Ar² is unsubstituted.A non-limiting example is the structure:

In one embodiment, D is hetCyc³ and E is Ar²C1-C6 alkyl. In oneembodiment, Ar² is phenyl which is unsubstituted. Non-limiting examplesinclude the structures:

In one embodiment, D is hetCyc³ and E is Ar²(C1-C3 alkyl)C(═O)— whereinthe alkyl portion is optionally substituted with one or two groupsindependently selected from the group consisting of OH, C1-C6 alkyl,hydroxyC1-C6 alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f)are independently H or C1-C6 alkyl or R^(e) and R^(f) together with thenitrogen to which they are attached form a 5-6 membered azacyclic ringoptionally having an additional ring heteroatom selected from N and O,and Ar² is as defined for General Formula I. In one embodiment, D ishetCyc³ and E is Ar²(C1-C3 alkyl)C(═O)— wherein the alkyl portion isunsubstituted. In one embodiment, Ar² is phenyl which is unsubstituted.A non-limiting example is the structure:

In one embodiment, D is hetCyc³ and E is R¹R²NC(═O)— where R¹ and R² areas defined for General Formula I. In one embodiment, R¹ is H or C1-C6alkyl and R² is H or C1-C6 alkyl optionally substituted with 1-3fluoros. Non-limiting examples include the structures:

In one embodiment, D is hetCyc³ and E is R¹R²N(C1-C3 alkyl)C(═O)—wherein the C1-C3 alkyl portion is optionally substituted with phenyl,and R¹ and R² are as defined for General Formula I. In one embodiment,R¹ is H or C1-C6 alkyl and R² is H or C1-C6 alkyl optionally substitutedwith 1-3 fluoros. A non-limiting example is the structure:

In one embodiment, D is hetCyc³ and E is R⁶C(═O)NH—, where R⁶ is C1-C6alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkoxy)C1-C6 alkyl,phenyl or hetCyc⁸. In one embodiment, R⁶ is C1-C6 alkoxy. A non-limitingexample is the structure:

In one embodiment, D is hetCyc³ and E is (C3-C6 cycloalkoxy)C(═O)—. Anon-limiting example is the structure:

In one embodiment, D is hetCyc³ and E is Ar⁴CH₂OC(═O)—. A non-limitingexample is the structure:

In one embodiment of Formula I, D is hetCyc⁹, where hetCyc⁹ is a fused9-10 membered heterocyclic ring having 1-3 ring nitrogen atoms andoptionally substituted with oxo

where the asterisk indicates the point of attachment to the E group.

In one embodiment, General Formula I includes compounds of Formula I-A,wherein X¹ is CH or CH₃, X² is CH, X³ is CH, and X³ is CH; and A, B, Dand E are as defined for General Formula I.

In one embodiment, General Formula I includes compounds of Formula I-B,wherein X¹ is N, CH or CH₃, X² is CH or N, X³ is CH or N, and X³ is CHor N, wherein one of X¹, X², X³ and X⁴ is N; and A, B, D and E are asdefined for General Formula I.

In one embodiment, General Formula I includes compounds of Formula I-C,wherein B is hetAr¹, wherein hetAr¹ is a 5-membered heteroaryl ringhaving 1-2 ring nitrogen atoms, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of C1-C6 alkyl, fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, and hydroxyC1-C6 alkyl; andX¹, X², X³, X⁴, A, D and E are as defined for General Formula I.

In one embodiment, General Formula I includes compounds of Formula I-D,wherein D is hetCyc¹ or hetCyc³, where hetCyc¹ is a 4-6 memberedheterocyclic ring having 1-2 ring atoms selected from N and O, whereinthe heterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C3alkyl, fluoroC1-C3 alkyl, difluoroC1-C3 alkyl, trifluoroC1-C3 alkyl, OH,or the heterocyclic ring is substituted with a C3-C6 cycloalkylidenering, or said heterocyclic ring is substituted with an oxo group;hetCyc³ is a 7-11 membered heterospirocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein the ring isoptionally substituted with C1-C3 alkyl; and X¹, X², X³, X⁴, A, B and Eare as defined for General Formula I. In one embodiment of Formula I-D,D is hetCyc¹.

In one embodiment of Formula I-D, D is hetCyc¹ where hetCyc¹ is a 5-6membered heterocyclic ring having 1-2 ring nitrogen atoms, wherein theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C3alkyl; and X¹, X², X³, X⁴, A, B and E are as defined for General FormulaI. In one embodiment of Formula I-D, D is hetCyc¹ where hetCyc¹ ispiperazinyl or piperidinyl, wherein the piperidinyl ring is optionallysubstituted with C1-C3 alkyl, and X¹, X², X³, X⁴, A, B and E are asdefined for General Formula I. In one embodiment of Formula I-D, D ishetCyc¹ where hetCyc¹ is piperazinyl, and X¹, X², X³, X⁴, A, B and E areas defined for General Formula I.

In one embodiment of Formula I-D, D is hetCyc³ wherein the hetCyc³ isoptionally substituted with C1-C3 alkyl, and X¹, X², X³, X⁴, A, B and Eare as defined for General Formula I. In one embodiment of Formula I-D,D is hetCyc³ wherein hetCyc³ is unsubstituted.

In one embodiment, Formula I includes compounds of Formula I-E, wherein:

X¹ is CH or N;

X² is CH or N;

X³ is CH;

X⁴ is CH;

wherein zero, one or two of X¹ and X² is N;

A is H, Cl or CN;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl, hydroxyC1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl,cyanoC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C1-C4 alkoxy)CH₂C(═O)—,(C1-C4 alkoxy)C(═O)C1-C3 alkyl, C3-C6 cycloalkyl, (R^(a)R^(b)N)C1-C6alkyl and hetCyc^(a);

D is hetCyc¹ or hetCyc³;

hetCyc¹ is a 4-6 membered heterocyclic ring having 1-2 ring nitrogenatoms, wherein the heterocyclic ring is optionally substituted with oneor more substituents independently selected from the group consisting ofC1-C3 alkyl, or said heterocyclic ring is substituted with an oxo group;

hetCyc³ is a 7-11 membered heterospirocyclic ring having 2 ring nitrogenatoms, wherein the ring is optionally substituted with C1-C3 alkyl;

E is

(a) hydrogen,

(d) C1-C6 alkyl optionally substituted with one to three fluoros,

(e) hydroxyC1-C6 alkyl optionally substituted with one to three fluoros,

(i) (C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros,

(j) (hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros,

(k) (C1-C6 alkoxy)C(═O)—,

(o) Cyc¹C(═O)—,

(r) hetCyc⁴C(═O)—,

(x) Ar²C1-C6 alkyl,

(y) (Ar²)hydroxy C2-C6 alkyl,

(z) Ar²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyC1-C6 alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f)are independently H or C1-C6 alkyl, or R^(e) and R^(f) together with thenitrogen to which they are attached form a 5-6 membered azacyclic ringoptionally having an additional ring heteroatom selected from N and O,

(cc) hetAr²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N—, where R^(e) and R^(f) are independently H or C1-C6 alkyl,R^(e) and R^(f) together with the nitrogen to which they are attachedform a 5-6 membered azacyclic ring optionally having an additional ringheteroatom selected from N and O,

(dd) R¹R²NC(═O)—,

(ee) R¹R²N(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with phenyl,

(ii) (C1-C6 alkyl)SO₂—, or

(mm) R⁶C(═O)NH—;

Cyc¹ is a C3-C6 cycloalkyl, wherein (a) the cycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of OH, halogen, C1-C6 alkoxy, CN, hydroxyC1-C6alkyl, (C1-C6 alkoxy)C1-C6 alkyl, and C1-C6 alkyl optionally substitutedwith 1-3 fluoros, or (b) the cycloalkyl is substituted with phenyl,wherein the phenyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C1-C3 alkyl, C1-C3 alkoxy and CF, or (c) the cycloalkyl issubstituted with a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N and O, wherein the heteroarylring is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C3alkyl, C1-C3 alkoxy and CF₃;

hetCyc⁴ is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N, O and S wherein said S is optionallyoxidized to SO₂ and is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, OH, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros),C1-C6 alkoxy, (C1-C6 alkoxy)C1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6alkyl)C(═O)—, a 5-6 membered heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, and phenyl wherein saidphenyl is optionally substituted with one or more substituents selectedfrom halogen, C1-C6 alkyl and C1-C6 alkoxy;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C6alkyl, C1-C6 alkoxy, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl,trifluoroC1-C6 alkyl, CN, a 5-6 membered heterocyclic ring having 1-2ring heteroatoms independently selected from N and O, and R^(i)R^(j)N—where R^(i) and R^(j) are independently H and C1-C6 alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S, and optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6alkoxy)C1-C6 alkyl, CN and R′R″N— where R′ and R″ are independently H orC1-C3 alkyl;

R¹ is H, C1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl;

R² is H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl (optionally substituted with 1-3 fluoros), Cyc³,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy(C(═O),hetCyc⁷, Ar³, Ar³C1-C3 alkyl-, hydroxyC1-C6 alkoxy or (C3-C6cycloalkyl)CH₂O—;

Cyc³ is a 3-6 membered carbocyclic ring optionally substituted with 1-2groups independently selected from the group consisting of C1-C6 alkoxy,OH and halogen;

Ar³ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy,fluoroC1-C3 alkyl, difluoroC1-C3 alkyl and trifluoroC1-C3 alkyl;

hetCyc⁷ is a 5-6 membered heterocyclic ring having a ring heteroatomselected from O and N wherein the ring is optionally substituted withC1-C6 alkyl;

R⁶ is C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, (C1-C6 alkoxy)C1-C6alkyl, phenyl or hetCyc⁸; and

hetCyc⁸ is a 5-6 membered heterocyclic ring having a ring heteroatomselected from O and N, wherein the heterocyclic ring is optionallysubstituted with C1-C6 alkyl.

In one embodiment of Formula I-E, hetAr¹ is a 5-membered heteroaryl ringhaving 1-2 ring nitrogen atoms, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of C1-C6 alkyl, fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl and hydroxyC1-C6 alkyl. In oneembodiment, B is pyrazolyl or imidazolyl optionally substituted withC1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6alkyl or hydroxyC1-C6 alkyl. In one embodiment, B is pyrazolyloptionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-E, hetCyc¹ is piperazinyl and E is (a)hydrogen, (d) C1-C6 alkyl optionally substituted with one to threefluoros, (e) hydroxyC1-C6 alkyl optionally substituted with one to threefluoros, (i) (C1-C6 alkyl)C(═O)— optionally substituted with one tothree fluoros, (j) (hydroxy C1-C6 alkyl)C(═O)— optionally substitutedwith one to three fluoros, (k) (C1-C6 alkoxy)C(═O)—, (o) Cyc¹C(═O)—, (r)hetCyc⁴C(═O)—, (x) Ar²C1-C6 alkyl, (y) (Ar²)hydroxy C2-C6 alkyl, (z)Ar²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N—, where R^(e) and R^(f) are independently H or C1-C6 alkyl,(cc) hetAr²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N—, where R^(e) and R^(f) are independently H or C1-C6 alkyl,(dd) R¹R²NC(═O)—, (ee) R¹R²N(C1-C3 alkyl)C(═O)— wherein the alkylportion is optionally substituted with phenyl, (ii) (C1-C6 alkyl)SO₂—,or (mm) R⁶C(═O)NH—. In some such embodiments, E is (d) C1-C6 alkyloptionally substituted with one to three fluoros, (e) hydroxyC1-C6 alkyloptionally substituted with one to three fluoros, (i) (C1-C6alkyl)C(═O)— optionally substituted with one to three fluoros, (j)(hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros, (o) Cyc¹C(═O)—, (r) hetCyc⁴C(═O)—, (x) Ar²C1-C6 alkyl, or (y)(Ar²)hydroxy C2-C6 alkyl.

In one embodiment of Formula I-E, hetCyc¹ is piperazinyl and E is (i)(C1-C6 alkyl)C(═O)— optionally substituted with one to three fluoros,(j) (hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros, or (r) hetCyc⁴C(═O)—.

In one embodiment of Formula I-E, hetCyc¹ is piperazinyl and E is(hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros.

In one embodiment of Formula I-E, hetCyc¹ is piperazinyl and E ishetCyc⁴C(═O)—. In one embodiment of Formula I-E, hetCyc¹ is piperazinyland E is hetCyc⁴C(═O)— where hetCyc⁴ is pyrrolidinyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, OH, CN, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), C1-C6 alkoxy and (C1-C6 alkoxy)C1-C6alkyl.

In one embodiment of Formula I-E, hetCyc¹ is piperazinyl and E ishetCyc⁴C(═O)—, where hetCyc⁴ is pyrrolidinyl optionally substituted withC1-C6 alkoxy.

In one embodiment of Formula I-E, hetCyc¹ is piperazinyl and E is (C1-C6alkyl)C(═O)— optionally substituted with one to three fluoros.

In one embodiment of Formula I-E, X¹ is N and each of X², X³ and X⁴ isCH.

In one embodiment of Formula I-E, A is CN.

In one embodiment of Formula I-E, A is Cl.

In one embodiment, Formula I includes compounds of Formula I-F, wherein:

X¹ is N and each of X², X³ and X⁴ is CH;

A is CN or Cl;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein the heteroaryl ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl andhydroxyC1-C6 alkyl;

D is hetCyc¹;

hetCyc¹ is piperazinyl;

E is (i) (C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros, (j) (hydroxy C1-C6 alkyl)C(═O)— optionally substituted with oneto three fluoros, or (r) hetCyc⁴C(═O)—; and

hetCyc⁴ is as defined for General Formula I.

In one embodiment of Formula I-F, hetAr¹ is pyrazolyl optionallysubstituted one or more substituents independently selected from thegroup consisting of C1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl,trifluoroC1-C6 alkyl and hydroxyC1-C6 alkyl. In one embodiment, B ispyrazolyl or imidazolyl optionally substituted with C1-C6 alkyl,fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl orhydroxyC1-C6 alkyl. In one embodiment of Formula I-F, hetAr¹ ispyrazolyl optionally substituted one or more substituents independentlyselected from the group consisting of C1-C6 alkyl. In one embodiment, Bis pyrazolyl or imidazolyl optionally substituted with C1-C6 alkyl,fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl orhydroxyC1-C6 alkyl.

In one embodiment of Formula I-F, hetCyc⁴ is a 5-membered heterocyclicring having a ring nitrogen atom, wherein the heterocyclic ring isoptionally substituted with C1-C6 alkoxy.

In one embodiment of Formula I-F, A is CN.

In one embodiment, Formula I includes compounds of Formula I-G, wherein:

X¹ is N and each of X², X³ and X⁴ is CH;

A is CN;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 2 ring nitrogen atoms,wherein the heteroaryl ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl andhydroxyC1-C6 alkyl;

D is hetCyc¹;

hetCyc¹ is piperazinyl;

E is (i) (C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros, (j) (hydroxy C1-C6 alkyl)C(═O)— optionally substituted with oneto three fluoros, or (r) hetCyc⁴C(═O)—; and

hetCyc⁴ is a 5-membered heterocyclic ring having a ring nitrogen atom,wherein the heterocyclic ring is optionally substituted with C1-C6alkoxy.

In one embodiment of Formula I-G, B is pyrazolyl optionally substitutedone or more substituents independently selected from the groupconsisting of C1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl,trifluoroC1-C6 alkyl and hydroxyC1-C6 alkyl. In one embodiment ofFormula I-G, B is pyrazolyl optionally substituted one or moresubstituents independently selected from the group consisting of C1-C6alkyl.

In one embodiment of Formula I-G, E is (i) (C1-C6 alkyl)C(═O)—optionally substituted with one to three fluoros.

In one embodiment of Formula I-G, E is (j) (hydroxy C1-C6 alkyl)C(═O)—optionally substituted with one to three fluoros.

In one embodiment of Formula I-G, E is (r) hetCyc⁴C(═O)—.

In one embodiment, Formula I includes compounds of Formula I-H wherein:

X¹ is N and each of X², X³ and X⁴ is CH;

A is CN;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein the heteroaryl ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl andhydroxyC1-C6 alkyl;

D is hetCyc³;

hetCyc³ is a 7-11 membered heterospirocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein the ring isoptionally substituted with C1-C3 alkyl; and

E is as defined for General Formula I.

In one embodiment of Formula I-H, E is (a) hydrogen; (e) hydroxyC1-C6alkyl optionally substituted with one to three fluoros; (i) (C1-C6alkyl)C(═O)— optionally substituted with one to three fluoros; (j)(hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros; (k) (C1-C6 alkoxy)C(═O)—; (o) Cyc¹C(═O)—; (w) Ar²C(═O)—; or (z)Ar²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N—, where R^(e) and R^(f) are independently H or C1-C6 alkyl;or (mm) R⁶C(═O)NH—.

In one embodiment of Formula I-H, E is (k) (C1-C6 alkoxy)C(═O)— or (o)Cyc¹C(═O)—.

In one embodiment, Formula I includes compounds of Formula I-I, wherein:

X¹, X², X³ and X⁴ are CH;

A is H, C1 or CN;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl, hydroxyC1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl,cyanoC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C1-C4 alkoxy)CH₂C(═O)—,(C1-C4 alkoxy)C(═O)C1-C3 alkyl, C3-C6 cycloalkyl, (R^(a)R^(b)N)C1-C6alkyl and hetCyc^(a);

D is hetCyc¹;

hetCyc¹ is a 5-6 membered heterocyclic ring having 1-2 ring nitrogenatoms, wherein the heterocyclic ring is optionally substituted with oneor more substituents independently selected from the group consisting ofC1-C3 alkyl;

E is

(a) hydrogen,

(i) (C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros,

(j) (hydroxy C1-C6 alkyl)C(═O)— optionally substituted with one to threefluoros,

(k) (C1-C6 alkoxy)C(═O)—,

(ee) R¹R²N(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with phenyl, or

(ii) (C1-C6 alkyl)SO₂;

R¹ is H or C1-C6 alkyl;

R² is H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6alkoxy)C1-C6 alkyl (optionally substituted with 1-3 fluoros), Cyc³,hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy(C(═O),hetCyc⁷, Ar³ or Ar³C1-C3 alkyl-;

Cyc³ is a 3-6 membered carbocyclic ring optionally substituted with 1-2groups independently selected from the group consisting of C1-C6 alkoxy,OH and halogen;

Ar³ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy,fluoroC1-C3 alkyl, difluoroC1-C3 alkyl and trifluoroC1-C3 alkyl; and

hetCyc⁷ is a 5-6 membered heterocyclic ring having a ring heteroatomselected from O and N wherein the ring is optionally substituted withC1-C6 alkyl.

In one embodiment of Formula I-I, hetAr¹ is a 5-membered heteroaryl ringhaving 2 ring nitrogen atoms, wherein the heteroaryl ring is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6alkyl, trifluoroC1-C6 alkyl and hydroxyC1-C6 alkyl.

In one embodiment, Formula I includes compounds of Formula I-I wherein

X¹ is N and each of X², X³ and X⁴ is CH;

A is CN or Cl;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms,wherein said heteroaryl ring is optionally substituted with one or moresubstituents independently selected from the group consisting of C1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl andhydroxyC1-C6 alkyl;

D is hetCyc¹;

hetCyc¹ is piperazinyl;

E is (d) C1-C6 alkyl optionally substituted with one to three fluoros,(e) hydroxyC1-C6 alkyl optionally substituted with one to three fluoros,(o) Cyc¹C(═O)—, (x) Ar²C1-C6 alkyl, (y) (Ar²)hydroxy C2-C6 alkyl, or(bb) (hetAr²)hydroxyC2-C6 alkyl; and

Ar² and hetAr² are as defined for General Formula I.

In one embodiment, Formula I includes compounds of Formula I-J, wherein:

X¹ is N and each of X², X³ and X⁴ is CH;

A is CN;

B is hetAr¹;

hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl, hydroxyC1-C6alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl,cyanoC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl, (C1-C4 alkoxy)CH₂C(═O)—,(C1-C4 alkoxy)C(═O)C1-C3 alkyl, C3-C6 cycloalkyl, (R^(a)R^(b)N)C1-C6alkyl, and hetCyc^(a);

D is hetCyc¹;

hetCyc¹ is piperazinyl;

E is (x) Ar²C1-C6 alkyl or (oo) hetAr²C1-C6 alkyl;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C1-C6alkyl, C1-C6 alkoxy (optionally substituted with 1-3 fluoros),fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, CN, a 5-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, and R^(i)R^(j)N— where R^(i) and R^(j) areindependently H and C1-C6 alkyl; and

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl, (C3-C6)cycloalkyl, (C1-C6alkoxy)C1-C6 alkyl, CN and R′R″N— where R′ and R″ are independently H orC1-C3 alkyl.

In one embodiment of Formula I-J, hetAr¹ is a 5-membered heteroaryl ringhaving 1-2 ring nitrogen atoms, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from the group consisting of C1-C6 alkyl, fluoroC1-C6 alkyl,difluoroC1-C6 alkyl, trifluoroC1-C6 alkyl and hydroxyC1-C6 alkyl. In oneembodiment, B is pyrazolyl or imidazolyl optionally substituted withC1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl, trifluoroC1-C6alkyl or hydroxyC1-C6 alkyl. In one embodiment, B is pyrazolyloptionally substituted with C1-C6 alkyl.

In one embodiment of Formula I-J, E is (x) Ar²C1-C6 alkyl or (oo)hetAr²C1-C6 alkyl. In one embodiment of Formula I-J, E is hetAr²C1-C6alkyl.

In one embodiment of Formula I-J, B is pyrazolyl optionally substitutedone or more substituents independently selected from the groupconsisting of C1-C6 alkyl, fluoroC1-C6 alkyl, difluoroC1-C6 alkyl,trifluoroC1-C6 alkyl and hydroxyC1-C6 alkyl. In one embodiment ofFormula I-J, B is pyrazolyl optionally substituted one or moresubstituents independently selected from the group consisting of C1-C6alkyl.

It will be appreciated that certain compounds provided herein maycontain one or more centers of asymmetry and may therefore be preparedand isolated in a mixture of isomers such as a racemic mixture, or in anenantiomerically pure form.

It will further be appreciated that the compounds of General Formula Ior their salts may be isolated in the form of solvates, and accordinglythat any such solvate is included within the scope of the presentinvention. For example, compounds of General Formula I and salts thereofcan exist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like.

The compounds of General Formula I include pharmaceutically acceptablesalts thereof. In addition, the compounds of General Formula I alsoinclude other salts of such compounds which are not necessarilypharmaceutically acceptable salts, and which may be useful asintermediates for preparing and/or purifying compounds of GeneralFormula I and/or for separating enantiomers of compounds of Formula I.Non-limiting examples of salts include monochloride, dichloride,trifluoroacetic acid, and di-trifluoroacetic acid salts of compounds ofFormula I.

In one embodiment, the compounds of General Formula I include thecompounds of Examples 1-567, 569-570, 572, 574-654, and 656-744 andstereoisomers and pharmaceutically acceptable salts and solvatesthereof. In one embodiment, the compounds of Examples 1-567, 569-570,572, 574-654, and 656-744 are in the free base form. In one embodiment,the compounds of Examples 1-567, 569-570, 572, 574-654, and 656-744 aremonochloride, dichloride, trifluoroacetic acid, or di-trifluoroaceticacid salts.

In some embodiments, the compounds provided herein exhibit potent andselective RET inhibition. For example, the compounds provided hereinexhibit nanomolar potency against wild type RET and select RET mutants,including the KIF5B-RET fusion and V804M gatekeeper mutation, withminimal activity against related kinases.

In some embodiments, the compounds of General Formula I or apharmaceutically acceptable salt or solvate thereof, selectively targeta RET kinase. For example, a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, can selectivelytarget a RET kinase over another kinase or non-kinase target.

In some embodiments, a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, exhibits at least a30-fold selectivity for a RET kinase over another kinase. For example, acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, exhibits at least a 40-fold selectivity; at least a50-fold selectivity; at least a 60-fold selectivity; at least a 70-foldselectivity; at least a 80-fold selectivity; at least a 90-foldselectivity; or at least 100-fold selectivity for a RET kinase overanother kinase. In some embodiments, selectivity for a RET kinase overanother kinase is measured in a cellular assay (e.g., a cellular assayas provided herein).

In some embodiments, the compounds provided herein can exhibitselectivity for a RET kinase over a KDR kinase (e.g., VEGFR2). In someembodiments, the selectivity for a RET kinase over a KDR kinase isobserved without loss of gatekeeper mutant potency. In some embodiments,the selectivity over a KDR kinase is at least 10-fold (e.g., at least a40-fold selectivity; at least a 50-fold selectivity; at least a 60-foldselectivity; at least a 70-fold selectivity; at least a 80-foldselectivity; at least a 90-fold selectivity; or at least 100-fold) ascompared to the inhibition of KIF5B-RET (i.e. the compounds were morepotent against KIF5B-RET than KDR). In some embodiments, the selectivityfor a RET kinase over a KDR kinase is about 30-fold. Without being boundby any theory, potent KDR kinase inhibition is believed to be a commonfeature among multikinase inhibitors (MKIs) that target RET and may bethe source of the dose-limiting toxicities observed with such compounds.

In some embodiments, inhibition of V804M was similar to that observedfor wild-type RET. For example, inhibition of V804M was within about2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of inhibitionof wild-type RET (i.e. the compounds were similarly potent againstwild-type RET and V804M). In some embodiments, the compounds providedherein exhibit selective cytotoxicity to RET-mutant cells.

In some embodiments, the compounds of General Formula I or apharmaceutically acceptable salt or solvate thereof, exhibit one or moreof high GI absorption, low clearance, and low potential for drug-druginteractions.

The term “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the patient beingtreated therewith.

Compounds provided herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. That is, an atom, in particular when mentioned in relation toa compound according to Formula I, comprises all isotopes and isotopicmixtures of that atom, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, when hydrogen is mentioned, it is understood to referto ¹H, ²H, ³H or mixtures thereof; when carbon is mentioned, it isunderstood to refer to ¹¹C, ¹²C, ¹³C, ¹⁴C or mixtures thereof; whennitrogen is mentioned, it is understood to refer to ¹³N, ¹⁴N, ¹⁵N ormixtures thereof; when oxygen is mentioned, it is understood to refer to¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluoro ismentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof.The compounds provided herein therefore also comprise compounds with oneor more isotopes of one or more atom, and mixtures thereof, includingradioactive compounds, wherein one or more non-radioactive atoms hasbeen replaced by one of its radioactive enriched isotopes. Radiolabeledcompounds are useful as therapeutic agents, e.g., cancer therapeuticagents, research reagents, e.g., assay reagents, and diagnostic agents,e.g., in vivo imaging agents. All isotopic variations of the compoundsprovided herein, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

For illustrative purposes, Schemes 1-4 show general methods forpreparing the compounds provided herein as well as key intermediates.For a more detailed description of the individual reaction steps, seethe Examples section below. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the inventivecompounds. Although specific starting materials and reagents aredepicted in the Schemes and discussed below, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a general scheme for the synthesis of compound 13 where Ais CN, and B, X¹, X², X³, X⁴, D and E are as defined for General FormulaI, and the synthesis of compound 13a where A is CN, D is as defined forGeneral Formula I provided that the D ring is coupled to the ringdefined by X¹, X², X³ and X⁴ through a ring nitrogen atom in the D ring,X¹, X², X³, X⁴ are as defined for Formula I provided that at least oneof X¹ and X² is nitrogen, and B, X³, X⁴, and E is as defined for GeneralFormula I.

Compound 2 is obtained by treating MSH reagent with3-bromo-5-methoxypyridine, which is commercially available. Theaminating reagent O-mesitylsulfonylhydroxylamine (MSH) may be preparedas described in Mendiola, J., et al., Org. Process Res. Dev. 2009,13(2), 263-267. Compound 2 may be reacted with ethyl propiolate toprovide the pyrazolo[1,5-a]pyridine a mixture of compounds 3A and 3B,which typically are obtained in a ratio of approximately 2:1 to 9:1. Themixture of compounds 3A and 3B may be treated with 48% HBr at elevatedtemperatures, followed by recrystallization or chromatographypurifications to isolate compound 4A as the minor isomer and compound 4Bas the major isomer.

The isolated compound 4B may be functionalized with a formyl group usingPOCl₃ followed by purification to provide compound 5. The formyl groupof compound 5 may be converted to an oxime group using NH₂OH to providecompound 6. The oxime group of compound 6 may be converted to a nitrilegroup using acetic anhydride to provide compound 7. The B group may beinstalled by treating compound 7 with a corresponding boronic esterhaving the formula hetAr¹—B(OR^(a))(OR^(b)) where hetAr¹ is as definedfor General Formula I and R^(a) and R^(b) are H or C1-C6 alkyl, or R^(a)and R^(b) together with the atoms to which they are connected form a 5-6membered ring optionally substituted with one to four C1-C3 alkylgroups, using appropriate palladium-catalyzed cross-coupling reactionconditions, e.g., Suzuki coupling reaction conditions (for example, apalladium catalyst and optionally a ligand in the presence of aninorganic base, for example, Pd₂(dba)₃, X-Phos and Na₂CO₃ in dioxane atelevated temperatures) to provide compound 8 where B is hetAr¹ asdefined for General Formula I. The methoxy group of compound 8 may beconverted to a hydroxy group by treating compound 8 with aluminumtrichloride to provide compound 9. The free hydroxy group of compound 9may be converted to a triflate group by treating compound 9 with atriflating reagent, for example1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamideto provide compound 10. Compound 12 may be prepared by coupling compound10 with the corresponding boronic ester compound 11 where Z is—B(OR^(a))(OR^(b)) and R^(a) and R^(b) are H or C1-C6 alkyl, or R^(a)and R^(b) together with the atoms to which they are connected form a 5-6membered ring optionally substituted with one to four C1-C3 alkylgroups, using appropriate palladium-catalyzed cross-coupling reactionconditions, e.g., Suzuki coupling reaction conditions (for example, apalladium catalyst and optionally a ligand in the presence of aninorganic base, for example, Pd₂(dba)₃, X-Phos and Na₂CO₃ in dioxane atelevated temperatures), wherein if the D ring of compound 11 comprisesan unsubstituted ring nitrogen atom, the nitrogen atom is protected withan appropriate amine protecting group prior to coupling. The protectinggroup if present on the D ring of compound 12 may be removed understandard conditions (for example, a Boc protecting group may be removedby treating compound 12 under acidic conditions, e.g., using HCl) toprovide compound 13 where E is H. Alternatively, the deprotected D ringmay be functionalized (i.e., reacted or treated with an appropriatereagent) to introduce the E group under standard conditions such asdescribed below to provide compound 13 where E is as defined for GeneralFormula I except that E is not H.

Alternatively, compound 10 may be coupled with compound 14 usingappropriate palladium-catalyzed cross-coupling reaction conditions,e.g., Suzuki coupling reaction conditions (for example, a palladiumcatalyst and optionally a ligand in the presence of an inorganic base,for example, Pd(PPh₃)₄ and Na₂CO₃) to provide compound 15. Compound 15may be reacted with compound 16 under appropriate SNAr conditions (forexample, optionally in the presence of a base such as K₂CO₃ and atelevated temperature) to provide compound 12a, wherein if the D ring ofcompound 16 comprises a second unsubstituted ring nitrogen atom, thesecond nitrogen atom is protected with an appropriate amine protectinggroup prior to coupling. The protecting group if present on the D ringof compound 12a may be removed under standard conditions (for example, aBoc group may be removed by treating compound 12a to acidic conditions,e.g., HCl) to provide compound 13a where E is H. Alternatively, thedeprotected D ring may be functionalized (i.e., reacted or treated withan appropriate reagent) to introduce the E group under standardconditions such as described below to provide compound 13a where E is asdefined for General Formula I except that E is not H.

Scheme 2 shows an alternative route for the synthesis of compound 13,wherein A is CN, and B, X¹, X², X³, X⁴, D and E are as defined forGeneral Formula I. Compound 4A (prepared as in Scheme 1) may befunctionalized with a formyl group using POCl₃ to provide compound 17.The formyl group may be converted to an oxime group using NH₂OH toprovide compound 18. The oxime group may be converted to a nitrile groupusing acetic anhydride to provide compound 19. The methoxy group ofcompound 19 may be converted to a hydroxy group by treating compound 19with aluminum trichloride to provide compound 20. Compound 21 may beprepared by coupling compound 20 with the corresponding boronic estercompound 11 where Z is —B(OR^(a))(OR^(b)) and R^(a) and R^(b) are H orC1-C6 alkyl, or R^(a) and R^(b) together with the atoms to which theyare connected form a 5-6 membered ring optionally substituted with oneto four C1-C3 alkyl groups, using appropriate palladium-catalyzedcross-coupling reaction conditions, e.g., Suzuki coupling reactionconditions (for example, a palladium catalyst and optionally a ligand inthe presence of an inorganic base, for example, Pd(PPh₃)₄ and Na₂CO₃ indioxane at elevated temperatures), wherein if the D ring of compound 11comprises an unsubstituted ring nitrogen atom, the nitrogen atom isprotected with an appropriate amine protecting group prior to coupling.The free hydroxy group of compound 21 may be converted to a triflategroup by treating compound 21 with a triflating reagent, for example1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamideto provide compound 22. The B group may be installed by treatingcompound 22 with the corresponding boronic ester having the formulahetAr¹—B(OR^(a))(OR^(b)) where hetAr¹ is as defined for General FormulaI and R^(a) and R^(b) are H or C1-C6 alkyl, or R^(a) and R^(b) togetherwith the atoms to which they are connected form a 5-6 membered ringoptionally substituted with one to four C1-C3 alkyl groups, usingappropriate palladium-catalyzed cross-coupling reaction conditions,e.g., Suzuki coupling reaction conditions (for example, a palladiumcatalyst and optionally a ligand in the presence of an inorganic base,for example, Pd₂(dba)₃, X-Phos and Na₂CO₃ in dioxane at elevatedtemperatures) to provide compound 12 where B is hetAr¹ as defined forGeneral Formula I. The protecting group if present on the D ring ofcompound 12 may be removed under standard conditions (for example, a Bocgroup may be removed by treating compound 12 to acidic conditions, e.g.,HCl in propan-2-ol) to provide compound 13 where E is H. Alternatively,the deprotected D ring may be functionalized (i.e., reacted or treatedwith an appropriate reagent) to introduce the E group under standardconditions such as described below to provide compound 13 where E is asdefined for General Formula I except that E is not H.

Scheme 3 shows a general scheme for the synthesis of compound 28 where Ais Cl, and B, X¹, X², X³, X⁴, D and E are as defined for General FormulaI. Compound 4B (prepared as in Scheme 1) may be chlorinated usingN-chlorosuccinimide to provide compound 23. The B group may be installedby coupling compound 23 with an appropriate boronic ester having theformula hetAr¹—B(OR^(a))(OR^(b)) where hetAr¹ is as defined for GeneralFormula I and R^(a) and R^(b) are H or C1-C6 alkyl, or R^(a) and R^(b)together with the atoms to which they are connected form a 5-6 memberedring optionally substituted with one to four C1-C3 alkyl groups, underappropriate palladium-catalyzed cross-coupling reaction conditions,e.g., Suzuki coupling reaction conditions (for example, a palladiumcatalyst and optionally a ligand in the presence of an inorganic base,for example, Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevated temperatures)to provide compound 24 where B is hetAr¹ as defined for General FormulaI. The methoxy group of compound 24 may be converted to a hydroxy groupunder standard conditions, for example by treating compound 24 withBBr₃, to yield compound 25. The free hydroxy group of compound 25 may beconverted to a triflate group by treating compound 25 with anappropriate triflating reagent in the presence of a base, e.g.,1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamideand DIEA to provide compound 26. Compound 27 may be prepared by couplingcompound 26 with the corresponding boronic ester compound 11 where Z is—B(OR^(a))(OR^(b)) and R^(a) and R^(b) are H or C1-C6 alkyl, or R^(a)and R^(b) together with the atoms to which they are connected form a 5-6membered ring optionally substituted with one to four C1-C3 alkylgroups, using under standard coupling conditions, e.g., Suzuki couplingreaction conditions (for example, a palladium catalyst and optionally aligand in the presence of an inorganic base, for example, Pd(PPh₃)₄ andNa₂CO₃ in dioxane at elevated temperatures), wherein if the D ring ofcompound 11 comprises an unsubstituted ring nitrogen atom, the nitrogenatom is protected with an appropriate amine protecting group prior tocoupling. The protecting group if present on the D ring of compound 27may be removed under standard conditions (for example, a Boc group maybe removed by treating compound 27 with acid (e.g., 5-6 N HCl inpropan-2-ol) to provide compound 28 where E is H. Alternatively, thedeprotected D ring may be functionalized (i.e., reacted or treated withan appropriate reagent) to introduce the E group under standardconditions such as described below to provide compound 28 where E is asdefined for General Formula I except that E is not H.

Scheme 4 shows a general scheme for the synthesis of compound 33,wherein A is H, and B, X¹, X², X³, X⁴, D and E are as defined forGeneral Formula I. Compound 4B (prepared as in Scheme 1) may be coupledwith an appropriate boronic ester having the formulahetAr¹—B(OR^(a))(OR^(b)) where hetAr¹ is as defined for General FormulaI and R^(a) and R^(b) are H or C1-C6 alkyl, or R^(a) and R^(b) togetherwith the atoms to which they are connected form a 5-6 membered ringoptionally substituted with one to four C1-C3 alkyl groups, underappropriate palladium-catalyzed cross-coupling reaction conditions,e.g., Suzuki coupling reaction conditions (for example, a palladiumcatalyst and optionally a ligand in the presence of an inorganic base,for example, Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevated temperatures)to install the B group to provide compound 29 where B is hetAr¹ asdefined for General Formula I. The methoxy group of compound 29 may beconverted to a hydroxy group by treating compound 29 with aluminumtrichloride to provide compound 30. The free hydroxy group of compound30 may be converted to a triflate group by treating compound 33 with atriflating reagent in the presence of a base, e.g.,1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamideand DIEA in an appropriate solvent such as THF to provide compound 31.Compound 32 may be prepared by coupling compound 31 with compound 11under appropriate palladium-catalyzed cross-coupling reactionconditions, e.g., Suzuki coupling reaction conditions (for example, apalladium catalyst and optionally a ligand in the presence of aninorganic base, for example, Pd(PPh₃)₄ and Na₂CO₃ in dioxane at elevatedtemperatures), wherein if the D ring of compound 11 comprises anunsubstituted ring nitrogen atom, the nitrogen atom is protected with anappropriate amine protecting group prior to coupling. The protectinggroup if present on the D ring of compound 32 may be removed understandard conditions (for example, a Boc group may be removed by treatingcompound 32 under acidic conditions, e.g., HCl in propan-2-ol) toprovide compound 33 where E is H. Alternatively, the deprotected D ringmay be functionalized (i.e., reacted or treated with an appropriatereagent) to introduce the E group under standard conditions such asdescribed below to provide compound 33 where E is as defined for GeneralFormula I except that E is not H.

The D ring of any one of compounds 13, 13a, 28, and 33 described inSchemes 1-4 may be functionalized (i.e., reacted or treated with anappropriate reagent) to introduce an E group, where E is any of the Egroups defined for General Formula I with the exception of hydrogen,using standard chemistry well known to persons skilled in the art. Asused herein, the term “functionalized” refers to a process step in whicha compound of Formula I where E is hydrogen is reacted or treated withan appropriate reagent to provide a compound of Formula I where E isother than hydrogen.

For example, an amide derivative (e.g., where D is hetCyc¹ where hetCyc¹is piperazinyl and E is (C1-C6 alkyl)C(═O)— optionally substituted withone to three fluoros; (hydroxy C1-C6 alkyl)C(═O)— optionally substitutedwith one to three fluoros; (C1-C6 alkoxy)(C1-C6 alkyl)C(═O)—;Cyc¹C(═O)—; Cyc¹(C1-C6 alkyl)C(═O)—; hetCyc⁴(C1-C3 alkyl)C(═O)—;Ar²C(═O)—; Ar²(C1-C3 alkyl)C(═O)— wherein the alkyl portion isoptionally substituted with one or two groups independently selectedfrom the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) are independently H andC1-C6 alkyl or R^(e) and R^(f) together with the nitrogen to which theyare attached form a 5-6 membered azacyclic ring optionally having anadditional ring heteroatom selected from N and O; hetAr²C(═O)—; orhetAr²(C1-C3 alkyl)C(═O)— wherein the alkyl portion is optionallysubstituted with one or two groups independently selected from the groupconsisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy andR^(e)R^(f)N—, where R^(e) and R^(f) are independently H or C1-C6 alkyl)or R^(e) and R^(f) together with the nitrogen to which they are attachedform a 5-6 membered azacyclic ring optionally having an additional ringheteroatom selected from N and O, may be obtained by treating compound13 having a deprotected amino D ring with an carboxylic acid (e.g., withan acid having the formula (C1-C6 alkyl)C(═O)OH optionally substitutedwith one to three fluoros; (hydroxy C1-C6 alkyl)C(═O)OH optionallysubstituted with one to three fluoros; (C1-C6 alkoxy)(C1-C6alkyl)C(═O)OH; Cyc¹C(═O)OH; Cyc¹(C1-C6 alkyl)C(═O)OH; hetCyc⁴(C1-C3alkyl)C(═O)OH; Ar²C(═O)OH; Ar²(C1-C3 alkyl)C(═O)OH wherein the alkylportion is optionally substituted with one or two groups independentlyselected from the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6alkyl, C1-C6 alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) areindependently H and C1-C6 alkyl or R^(e) and R^(f) together with thenitrogen to which they are attached form a 5-6 membered azacyclic ringoptionally having an additional ring heteroatom selected from N and O;hetAr²C(═O)OH; or hetAr²(C1-C3 alkyl)C(═O)OH wherein the alkyl portionis optionally substituted with one or two groups independently selectedfrom the group consisting of OH, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6alkoxy and R^(e)R^(f)N—, where R^(e) and R^(f) are independently H orC1-C6 alkyl) or R^(e) and R^(f) together with the nitrogen to which theyare attached form a 5-6 membered azacyclic ring optionally having anadditional ring heteroatom selected from N and O) using conventionalamide bond formation conditions, for example by treating the carboxylicacid with an activating agent (e.g., HATU), followed by addition of thecompound 13 having a deprotected amino D ring in the presence of a base(e.g., an amine base such as DIEA) in an appropriate solvent (such asDMA) to provide a functionalized compound 13. The same chemistry may beutilized with compounds 13a, 28 and 33 to prepare functionalizedcompounds 13a, 28 and 33, respectively.

As another example, a urea derivative (e.g., where D is hetCyc¹ wherehetCyc¹ is piperazinyl and E is hetCyc⁴C(═O)— or R¹R²NC(═O)—) may beprepared by first activating a ring nitrogen in the D ring of compound13 with triphosgene in the presence of DIEA and in a solvent such asDCM, followed by addition of a primary or secondary amine reagent (e.g.,a reagent having the formula hetCyc⁴NH₂ or R¹R²NH) to provide afunctionalized compound 13. The same chemistry may be utilized withcompounds 13a, 28 and 33 to prepare functionalized compounds 13a, 28 and33, respectively.

As another example, an N-alkyl derivative (e.g., where D is hetCyc¹where hetCyc¹ is piperazinyl and E is hydroxyC1-C6 alkyl optionallysubstituted with one to three fluoros; (C1-C6 alkoxy)hydroxy C1-C6alkyl; Ar²C1-C6 alkyl; (Ar²)hydroxy C2-C6 alkyl; or (hetAr²)hydroxyC2-C6alkyl, may be prepared by treating compound 13 where E is H with analkyl bromide or alkyl chloride (e.g., hydroxyC1-C6 alkyl-X optionallysubstituted with one to three fluoros; (C1-C6 alkoxy)hydroxy C1-C6alkyl-X; Ar²C1-C6 alkyl-X; (Ar²)hydroxy C2-C6 alkyl-X; or(hetAr²)hydroxyC2-C6 alkyl-X where X is Br or C1) or an epoxide in thepresence of a base such as DIEA in a solvent at ambient or elevatedtemperatures) to provide a functionalized compound 13. The samechemistry may be utilized with compounds 13a, 28 and 33 to preparefunctionalized compounds 13a, 28 and 33, respectively.

As another example, a compound of Formula I wherein D is hetCyc¹ (wherehetCyc¹ is a 4-6 membered heterocyclic ring having 2 ring nitrogenatoms, wherein the heterocyclic ring is optionally substituted with oneor more substituents independently selected from the group consisting ofC1-C3 alkyl, fluoroC1-C3 alkyl, difluoroC1-C3 alkyl, trifluoroC1-C3alkyl and OH, or said heterocyclic ring is substituted with a C3-C6cycloalkylidene ring, or said heterocyclic ring is substituted with anoxo group) and E is Ar²C1-C6 alkyl, hetAr²C1-C6 alkyl, (hetCyc⁴)C1-C6alkyl, or (C3-C6 cycloalkoxy)C1-C6 alkyl, may be prepared by treatingcompound 13 where E is H (wherein E is on a ring nitrogen atom ofhetCyc¹) with an appropriate aldehyde having the formula Ar²(C1-C5alkyl)C(═O)H, hetAr²(C1-C5 alkyl)C(═O)H, (hetCyc⁴)(C1-C5 alkyl)C(═O)H,or (C3-C6 cycloalkoxy)(C1-C5 alkyl)C(═O)H under standard reductiveamination reaction conditions, for example in the presence of a base anda reducing agent, for example in the presence of a reducing agent suchas sodium triacetoxyborohydride or sodium cyanoborohydride.

As another example, a sulfonamide derivative may be prepared by treatingcompound 13 where E is H with an appropriate sulfonyl chloride in thepresence of a base, such as an amine base (such as triethylamine) in anappropriate solvent to provide a functionalized compound 13. The samechemistry may be utilized with compounds 13a, 28 and 33 to preparefunctionalized compounds 13a, 28 and 33, respectively.

Further provided herein is a process for preparing of a compound ofGeneral Formula I or a pharmaceutically acceptable salt thereof asdefined herein which comprises:

(a) for a compound of General Formula I where E is H and A, B, X¹, X²,X³, X⁴, and D are as defined for General Formula I, coupling acorresponding compound having the formula

where A and B are as defined for General Formula I, with a correspondingcompound having the formula 11

in the presence of a palladium catalyst and optionally a ligand and inthe presence of a base, where Z is —B(OR^(a))(OR^(b)) and R^(a) andR^(b) are H or (1-6C)alkyl, or R^(a) and R^(b) together with the atomsto which they are connected form a 5-6 membered ring optionallysubstituted with 1-4 substituents selected from (C1-C3 alkyl), the

ring is as defined for hetCyc¹, hetCyc² and hetCyc³ of Formula I, andX¹, X², X³ and X⁴ are as defined for General Formula I, followed byremoval of a protecting group on the D ring if present; or

(b) for a compound of General Formula I where A, B, X¹, X², X³, X⁴, Dand E are as defined for General Formula I with the exception that E isnot hydrogen, functionalizing a corresponding compound having theformula

wherein the

moiety is as defined for hetCyc¹, hetCyc² and hetCyc³ of Formula I, andA, B, X¹, X², X³ and X⁴ are as defined for General Formula I; or

(c) for a compound of General Formula I where A is CN, D is as definedfor General Formula I provided that the D ring is coupled to the ringdefined by X¹, X², X³ and X⁴ through a ring nitrogen atom in the D ring,X¹, X², X³, X⁴ are as defined for Formula I provided that at least oneof X¹ and X² is nitrogen, and E is as defined for General Formula I,reacting a corresponding compound having the formula 15

where B, X¹, X², X³ and X⁴ are as defined for General Formula I providedthat at least one of X¹ and X² is nitrogen, with a correspondingcompound having the formula 17

in the presence of a base, wherein the

ring is as defined for hetCyc¹, hetCyc² and hetCyc³ of Formula I; or

(d) for a compound of General Formula I where A is CN, E is H, and B,X¹, X², X³, X⁴, and D are as defined for General Formula I, reacting acompound having the formula 22

where X¹, X², X³, X⁴ and D are as defined for General Formula I, with acorresponding boronic ester having the formula

where hetAr¹ is as defined for General Formula I and R^(a) and R^(b) areH or CC6 alkyl, or R^(a) and R^(b) together with the atoms to which theyare connected form a 5-6 membered ring optionally substituted with oneto four C1-C3 alkyl substituents, in the presence of a palladiumcatalyst and optionally a ligand and in the presence of a base; and

removing any protecting groups and optionally forming a pharmaceuticallyacceptable salt thereof.

Referring to processes (a) and (d), suitable palladium catalysts includePd(PPh₃)₄, Pd₂(dba)₃, Pd(OAc)₂, and Pd(PPh₃)₂Cl₂. Suitable ligandsinclude X-PHOS (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl),DIPHOS (1,2-Bis(diphenylphosphino)ethane) or rac-BINAP(racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl). The base may be,for example, an alkali metal carbonate, hydroxide, alkoxide or acetate,such as for example cesium carbonate, sodium carbonate, potassiumcarbonate, sodium hydroxide, sodium tert-butoxide or potassium acetate.Convenient solvents include aprotic solvents such as ethers (for exampletetrahydrofuran or p-dioxane), toluene, DMF or DME. The reaction can beconveniently performed at a temperature ranging from ambient temperatureto 120° C., for example from 80 to 110° C.

The ability of test compounds to act as RET inhibitors may bedemonstrated by the assay described in Example A. IC₅₀'s are shown inTable 5.

Compounds of General Formula I have been found to be inhibitors of a RETkinase, and are useful for treating diseases and disorders which can betreated with a RET kinase inhibitor, such as RET-associated diseases anddisorders, e.g., proliferative disorders such as cancers, includinghematological cancers and solid tumors, and gastrointestinal disorderssuch as IBS.

As used herein, terms “treat” or “treatment” refer to therapeutic orpalliative measures. Beneficial or desired clinical results include, butare not limited to, alleviation, in whole or in part, of symptomsassociated with a disease or disorder or condition, diminishment of theextent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state (e.g., one or more symptoms of the disease), andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment.

As used herein, the term “subject,” “individual,” or “patient,” usedinterchangeably, refers to any animal, including mammals such as mice,rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,primates, and humans. In some embodiments, the patient is a human. Insome embodiments, the subject has experienced and/or exhibited at leastone symptom of the disease or disorder to be treated and/or prevented.In some embodiments, the subject has been identified or diagnosed ashaving a cancer with dysregulation of a RET gene, a RET protein, orexpression or activity, or level of any of the same (a RET-associatedcancer) (e.g., as determined using a regulatory agency-approved, e.g.,FDA-approved, assay or kit). In some embodiments, the subject has atumor that is positive for dysregulation of a RET gene, a RET protein,or expression or activity, or level of any of the same (e.g., asdetermined using a regulatory agency-approved assay or kit). The subjectcan be a subject with a tumor(s) that is positive for dysregulation of aRET gene, a RET protein, or expression or activity, or level of any ofthe same (e.g., identified as positive using a regulatoryagency-approved, e.g., FDA-approved, assay or kit). The subject can be asubject whose tumors have dysregulation of a RET gene, a RET protein, orexpression or activity, or a level of the same (e.g., where the tumor isidentified as such using a regulatory agency-approved, e.g.,FDA-approved, kit or assay). In some embodiments, the subject issuspected of having a RET-associated cancer. In some embodiments, thesubject has a clinical record indicating that the subject has a tumorthat has dysregulation of a RET gene, a RET protein, or expression oractivity, or level of any of the same (and optionally the clinicalrecord indicates that the subject should be treated with any of thecompositions provided herein). In some embodiments, the patient is apediatric patient.

The term “pediatric patient” as used herein refers to a patient underthe age of 21 years at the time of diagnosis or treatment. The term“pediatric” can be further be divided into various subpopulationsincluding: neonates (from birth through the first month of life);infants (1 month up to two years of age); children (two years of age upto 12 years of age); and adolescents (12 years of age through 21 yearsof age (up to, but not including, the twenty-second birthday)). BerhmanR E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics,15th Ed. Philadelphia: W. B. Saunders Company, 1996; Rudolph A M, et al.Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins;1994. In some embodiments, a pediatric patient is from birth through thefirst 28 days of life, from 29 days of age to less than two years ofage, from two years of age to less than 12 years of age, or 12 years ofage through 21 years of age (up to, but not including, the twenty-secondbirthday). In some embodiments, a pediatric patient is from birththrough the first 28 days of life, from 29 days of age to less than 1year of age, from one month of age to less than four months of age, fromthree months of age to less than seven months of age, from six months ofage to less than 1 year of age, from 1 year of age to less than 2 yearsof age, from 2 years of age to less than 3 years of age, from 2 years ofage to less than seven years of age, from 3 years of age to less than 5years of age, from 5 years of age to less than 10 years of age, from 6years of age to less than 13 years of age, from 10 years of age to lessthan 15 years of age, or from 15 years of age to less than 22 years ofage.

In certain embodiments, compounds of General Formula I are useful forpreventing diseases and disorders as defined herein (for example,autoimmune diseases, inflammatory diseases, and cancer). The term“preventing” as used herein means the prevention of the onset,recurrence or spread, in whole or in part, of the disease or conditionas described herein, or a symptom thereof.

The term “RET-associated disease or disorder” as used herein refers todiseases or disorders associated with or having a dysregulation of a RETgene, a RET kinase (also called herein RET kinase protein or RETkinase), or the expression or activity or level of any (e.g., one ormore) of the same (e.g., any of the types of dysregulation of a RETgene, a RET kinase, a RET kinase domain, or the expression or activityor level of any of the same described herein). Non-limiting examples ofa RET-associated disease or disorder include, for example, cancer andgastrointestinal disorders such as irritable bowel syndrome (IBS).

The term “RET-associated cancer” as used herein refers to cancersassociated with or having a dysregulation of a RET gene, a RET kinase(also called herein RET kinase protein or RET kinase), or expression oractivity, or level of any of the same. Non-limiting examples of aRET-associated cancer are described herein.

The phrase “dysregulation of a RET gene, a RET kinase, or the expressionor activity or level of any of the same” refers to a genetic mutation(e.g., a RET gene translocation that results in the expression of afusion protein, a deletion in a RET gene that results in the expressionof a RET protein that includes a deletion of at least one amino acid ascompared to the wild-type RET protein, or a mutation in a RET gene thatresults in the expression of a RET protein with one or more pointmutations, or an alternative spliced version of a RET mRNA that resultsin a RET protein that results in the deletion of at least one amino acidin the RET protein as compared to the wild-type RET protein), or a RETgene amplification that results in overexpression of a RET protein or anautocrine activity resulting from the overexpression of a RET gene acell, that results in a pathogenic increase in the activity of a kinasedomain of a RET protein (e.g., a constitutively active kinase domain ofa RET protein) in a cell. As another example, a dysregulation of a RETgene, a RET protein, or expression or activity, or level of any of thesame, can be a mutation in a RET gene that encodes a RET protein that isconstitutively active or has increased activity as compared to a proteinencoded by a RET gene that does not include the mutation. For example, adysregulation of a RET gene, a RET protein, or expression or activity,or level of any of the same, can be the result of a gene or chromosometranslocation which results in the expression of a fusion protein thatcontains a first portion of RET that includes a functional kinasedomain, and a second portion of a partner protein (i.e., that is notRET). In some examples, dysregulation of a RET gene, a RET protein, orexpression or activity, can be a result of a gene translation of one RETgene with another RET gene. Non-limiting examples of fusion proteins aredescribed in Table 1. Non-limiting examples of RET kinase protein pointmutations/insertions are described in Table 2. Additional examples ofRET kinase protein point mutations are RET inhibitor resistancemutations. Non-limiting examples of RET inhibitor resistance mutationsare described in Tables 3 and 4.

The term “wildtype” or “wild-type” describes a nucleic acid (e.g., a RETgene or a RET mRNA) or protein (e.g., a RET protein) that is found in asubject that does not have a RET-associated disease, e.g., aRET-associated cancer (and optionally also does not have an increasedrisk of developing a RET-associated disease and/or is not suspected ofhaving a RET-associated disease), or is found in a cell or tissue from asubject that does not have a RET-associated disease, e.g., aRET-associated cancer (and optionally also does not have an increasedrisk of developing a RET-associated disease and/or is not suspected ofhaving a RET-associated disease).

The term “regulatory agency” refers to a country's agency for theapproval of the medical use of pharmaceutical agents with the country.For example, a non-limiting example of a regulatory agency is the U.S.Food and Drug Administration (FDA).

Provided herein is a method of treating cancer (e.g., a RET-associatedcancer) in a patient in need of such treatment, the method comprisingadministering to the patient a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof or a pharmaceutical composition thereof.

In some embodiments of any of the methods or uses described herein, thecancer (e.g., RET-associated cancer) is a hematological cancer. In someembodiments of any of the methods or uses described herein, the cancer(e.g., RET-associated cancer) is a solid tumor. In some embodiments ofany of the methods or uses described herein, the cancer (e.g.,RET-associated cancer) is lung cancer (e.g., small cell lung carcinomaor non-small cell lung carcinoma), papillary thyroid cancer, medullarythyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer,refractory differentiated thyroid cancer, lung adenocarcinoma,bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroidhyperplasia, breast cancer, colorectal cancer (e.g., metastaticcolorectal cancer), papillary renal cell carcinoma, ganglioneuromatosisof the gastroenteric mucosa, inflammatory myofibroblastic tumor, orcervical cancer. In some embodiments of any of the methods or usesdescribed herein, the cancer (e.g., RET-associated cancer) is selectedfrom the group of: acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), cancer in adolescents, adrenocortical carcinoma, analcancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor,basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer,brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkittlymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumors,cervical cancer, childhood cancers, chordoma, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyeloproliferative neoplasms, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductalcarcinoma in situ, embryonal tumors, endometrial cancer, ependymoma,esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranialgerm cell tumor, extragonadal germ cell tumor, extrahepatic bile ductcancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone,gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia,head and neck cancer, heart cancer, hepatocellular cancer,histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocularmelanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposisarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer,leukemia, lip and oral cavity cancer, liver cancer, lung cancer,lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone,osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma,metastatic squamous neck cancer, midline tract carcinoma, mouth cancer,multiple endocrine neoplasia syndromes, multiple myeloma, mycosisfungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferativeneoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma,myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-smallcell lung cancer, oral cancer, oral cavity cancer, lip cancer,oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer,papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma,pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma,pregnancy and breast cancer, primary central nervous system lymphoma,primary peritoneal cancer, prostate cancer, rectal cancer, renal cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer,sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamousneck cancer, stomach cancer, T-cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, unknown primary carcinoma,urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, and Wilms' tumor.

In some embodiments, a hematological cancer (e.g., hematological cancersthat are RET-associated cancers) is selected from the group consistingof leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease(also called Hodgkin's lymphoma), and myeloma, for instance, acutelymphocytic leukemia (ALL), acute myeloid leukemia (AML), acutepromyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML),chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia(AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia(PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AMLwith trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL),myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD),and multiple myeloma (MM). Additional examples of hematological cancersinclude myeloproliferative disorders (MPD) such as polycythemia vera(PV), essential thrombocytopenia (ET) and idiopathic primarymyelofibrosis (IMF/IPF/PMF). In one embodiment, the hematological cancer(e.g., the hematological cancer that is a RET-associated cancer) is AMLor CMML.

In some embodiments, the cancer (e.g., the RET-associated cancer) is asolid tumor. Examples of solid tumors (e.g., solid tumors that areRET-associated cancers) include, for example, thyroid cancer (e.g.,papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer(e.g., lung adenocarcinoma, small-cell lung carcinoma), pancreaticcancer, pancreatic ductal carcinoma, breast cancer, colon cancer,colorectal cancer, prostate cancer, renal cell carcinoma, head and necktumors, neuroblastoma, and melanoma. See, for example, Nature ReviewsCancer, 2014, 14, 173-186.

In some embodiments, the cancer is selected from the group consisting oflung cancer, papillary thyroid cancer, medullary thyroid cancer,differentiated thyroid cancer, recurrent thyroid cancer, refractorydifferentiated thyroid cancer, multiple endocrine neoplasia type 2A or2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroidhyperplasia, breast cancer, colorectal cancer, papillary renal cellcarcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervicalcancer.

In some embodiments, the patient is a human.

Compounds of General Formula I and pharmaceutically acceptable salts andsolvates thereof are also useful for treating a RET-associated cancer.

Accordingly, also provided herein is a method for treating a patientdiagnosed with or identified as having a RET-associated cancer, e.g.,any of the exemplary RET-associated cancers disclosed herein, comprisingadministering to the patient a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition thereof as definedherein.

Dysregulation of a RET kinase, a RET gene, or the expression or activityor level of any (e.g., one or more) of the same can contribute totumorigenesis. For example, a dysregulation of a RET kinase, a RET gene,or expression or activity or level of any of the same can be atranslocation, overexpression, activation, amplification, or mutation ofa RET kinase, a RET gene, or a RET kinase domain. Translocation caninclude translocations involving the RET kinase domain, mutations caninclude mutations involving the RET ligand-binding site, andamplification can be of a RET gene. Other dysregulations can include RETmRNA splice variants and RET autocrine/paracrine signaling, which canalso contribute to tumorigenesis.

In some embodiments, the dysregulation in a RET gene, a RET kinase, orexpression or activity or level of any of the same, includesoverexpression of wild-type RET kinase (e.g., leading to autocrineactivation). In some embodiments, the dysregulation in a RET gene, a RETkinase protein, or expression or activity or level of any of the same,includes overexpression, activation, amplification, or mutation in achromosomal segment comprising the RET gene or a portion thereof,including for example the kinase domain portion, or a portion capable ofexhibiting kinase activity.

In some embodiments, the dysregulation of a RET gene, a RET kinaseprotein, or expression or activity or level of any of the same, includesone or more chromosome translocations or inversions resulting in a RETgene fusions. In some embodiments, the dysregulation of a RET gene, aRET kinase protein, or expression or activity or level of any of thesame, is a result of genetic translocations in which the expressedprotein is a fusion protein containing residues from a non-RET partnerprotein, and includes a minimum of a functional RET kinase domain.

Non-limiting examples of RET fusion proteins are shown in Table 1.

TABLE 1 Exemplary RET Fusion Partners and Cancers Non-limiting ExemplaryRET- Fusion Partner Associated Cancer(s) BCR Chronic MyelomonocyticLeukemia (CMML) CLIP1 Adenocarcinoma KIF5B NSCLC, Ovarian Cancer,Spitzoid Neoplasms; Lung Adenocarcinoma^(3, 4, 14); AdenosquamousCarcinomas¹⁵ CCDC6 (also NSCLC, Colon Cancer, called PTC1, PapillaryThyroid Cancer; D10S170, or H4) Adenocarcinomas; Lung Adenocarcinoma;Metastatic Colorectal Cancer⁵; Adenosquamous Carcinomas¹⁵ PTC1ex9Metastatic papillary thyroid cancer² NCOA4 (also Papillary ThyroidCancer, called PTC3, NSCLC, Colon Cancer, ELE1, and RFG) Salivary GlandCancer, Metastatic Colorectal Cancer⁵; Lung Adenocarcinoma¹⁵;Adenosquamous Carcinomas¹⁵ Diffuse Sclerosing Variant of PapillaryThyroid Cancer¹⁶ TRIM33 (also NSCLC, Papillary Thyroid called PTC7 andCancer RFG7) ERC1 (also called Papillary Thyroid Cancer, ELKS) BreastCancer FGFR1OP CMML, Primary Myelofibrosis with secondary Acute MyeloidLeukemia MBD1(also known Papillary Thyroid Cancer as PCM1) RAB61P2Papillary Thyroid Cancer PRKAR1A (also Papillary Thyroid Cancer calledPTC2) TRIM24 (also Papillary Thyroid Cancer called PTC6) KTN1 (alsocalled Papillary Thyroid Cancer PTC8) GOLGA5 (also Papillary ThyroidCancer, called PTC5) Spitzoid Neoplasms HOOK3 Papillary Thyroid CancerKIAA1468 (also Papillary Thyroid Cancer, called PTC9 and LungAdenocarcinoma⁸ RFG9) TRIM27 (also Papillary Thyroid Cancer called RFP)AKAP13 Papillary Thyroid Cancer FKBP15 Papillary Thyroid Cancer SPECC1LPapillary Thyroid Cancer; Thyroid Gland Carcinoma TBL1XR1 PapillaryThyroid Cancer; Thyroid Gland Carcinoma CEP55 Diffuse Gastric Cancer⁷CUX1 Lung Adenocarcinoma KIAA1468 Lung Adenocarcinoma¹² ACBD5 PapillaryThyroid Carcinoma MYH13 Medullary Thyroid Carcinoma¹ UncharacterizedInflammatory Myofibroblastic Tumor⁶ PIBF1 Bronchiolus Lung CellCarcinoma⁹ KIAA1217 Papillary Thyroid Cancer^(10, 13) LungAdenocarcinoma¹⁴ NSCLC¹⁴ MPRIP NSCLC¹¹ ¹Grubbs et al., J. Clin.Endocrinol. Metab. 100: 788-793, 2015. ²Halkova et al., Human Pathology46: 1962-1969, 2015. ³U.S. Pat. No. 9,297,011 ⁴U.S. Pat. No. 9,2161,72⁵Le Rolle et al., Oncotarget. 6(30): 28929-37, 2015. ⁶Antonescu et al.,Am J Surg Pathol. 39(7): 957-67, 2015. ⁷U.S. patent applicationPublication No. 2015/0177246. ⁸U.S. patent application Publication No.2015/0057335. ⁹Japanese patent application Publication No. 2015/109806A.¹⁰Chinese patent application Publication No. 105255927A. ¹¹Fang, et al.Journal of Thoracic Oncology 11.2 (2016): S21-S22. ¹²European patentapplication Publication No. EP3037547A1. ¹³Lee et al., Oncotarget. DOI:10.18632/oncotarget.9137, e-published ahed of printing, 2016. ¹⁴Saito etal., Cancer Science 107: 713-720, 2016. ¹⁵Pirker et al., Transl. LungCancer Res. 4(6): 797-800, 2015 ¹⁶Joung et al., Histopathology 69(1):45-53, 2016

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes one or moredeletions (e.g., deletion of an amino acid at position 4), insertions,or point mutation(s) in a RET kinase. In some embodiments, thedysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, includes a deletion of one or more residuesfrom the RET kinase, resulting in constitutive activity of the RETkinase domain.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a RET gene that results in the production of a RETkinase that has one or more amino acid substitutions as compared to thewild-type RET kinase (see, for example, the missense point mutationslisted in Table 2).

TABLE 2 Activating RET Kinase Protein PointMutations/Insertions/Deletions Exemplary RET Point Mutations Amino acidposition 2 Amino acid position 3 Amino acid position 4 Amino acidposition 5 Amino acid position 6 Amino acid position 7 Amino acidposition 8 Amino acid position 11 Amino acid position 12 Amino acidposition 13 Amino acid position 20 Amino acid position 32 (e.g., S32L)Amino acid position 34 (e.g., D34S) Amino acid position 40 (e.g., L40P)Amino acid position 64 (e.g., P64L) Amino acid position 67 (e.g., R67H)Amino acid position 114 (e.g., R114H) Amino acid position 136 (e.g.,glutamic acid to stop codon) Amino acid position 145 (e.g., V145G) Aminoacid position 180 (e.g., arginine to stop codon) Amino acid position 200Amino acid position 292 (e.g., V292M) Amino acid position 294 Amino acidposition 321 (e.g., G321R) Amino acid position 330 (e.g., R330Q) Aminoacid position 338 (e.g., T338I) Amino acid position 360 (e.g., R360W)Amino acid position 373 (e.g., alanine to frameshift) Amino acidposition 393 (e.g., F393L) Amino acid position 432 Δ Amino acid residues505-506 (6-Base Pair In-Frame Germline Deletion in Exon 7)³ Amino acidposition 510 (e.g., A510V) Amino acid position 511 (e.g., E511K) Aminoacid position 513 (e.g., A513D)⁷* Amino acid position 515 (e.g., C515S,C515W⁴) Amino acid position 525 (e.g., R525W)⁷* Amino acid position 531(e.g., C531R, or 9 base pair duplication²) Amino acid position 532(e.g., duplication)² Amino acid position 533 (e.g., G533C¹², G533S)Amino acid position 550 (e.g., G550E) Amino acid position 591 (e.g.,V591I) Amino acid position 593 (e.g., G593E) Amino acid position 600(e.g., R600Q) Amino acid position 602 (e.g., 1602V)⁶ Amino acid position603 (e.g., K603Q, K603E²) Amino acid position 606 (e.g., Y606C) Aminoacid position 609 (e.g., C609Y, C609S, C609G, C609R, C609F, C609W) Aminoacid position 611 (e.g., C611R, C611S, C611G, C611Y, C611F, C611W) Aminoacid position 618 (e.g., C618S, C618Y, C618R, C618Y, C618G, C618F,C618W) Amino acid position 619 (e.g., F619F) Amino acid position 620(e.g., C620S, C620W, C620R, C620G, C620L, C620Y, C620F) Amino acidposition 623 (e.g., E623K) Amino acid position 624 (e.g., D624N) Aminoacid position 630 (e.g., C630A, C630R, C630S, C630Y, C630F) Amino acidposition 631 (e.g., D631N, D631Y, D631A, D631G, D631V, D631E, ) Aminoacid position 632 (e.g., E632K, E632G^(5, 11)) Δ Amino acid residues632-633 (6-Base Pair In-Frame Germline Deletion in Exon 11)⁹ Amino acidposition 633 (e.g., 9 base pair duplication²) Amino acid position 634(e.g., C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, or C634T,or an insertion ELCR², or a 12 base pair duplication²) (e.g., causingMTC) Amino acid position 635 (e.g., R635G) Amino acid position 636(e.g., T636P², T636M⁴) Amino acid position 640 (e.g., A640G) Amino acidposition 641 (e.g., A641S, A641T⁸) Amino acid position 648 (e.g., V648I)Amino acid position 649 (e.g., S649L) Amin acid position 664 (e.g.,A664D) Amino acid position 665 (e.g., H665Q) Amino acid position 666(e.g., K666E, K666M, K666N) Amino acid position 686 (e.g., S686N) Aminoacid position 691 (e.g., G691S) Amino acid position 694 (e.g., R694Q)Amino acid position 700 (e.g., M700L) Amino acid position 706 (e.g.,V706M, V706A) Amino acid position 713 splice variant (e.g., E713K)⁶Amino acid position 736 (e.g., G736R)⁶ Amino acid position 748 (e.g.,G748C) Amino acid position 750 (e.g., A750P) Amino acid position 765(e.g., S765P) Amino acid position 766 (e.g., P766S, P766M⁶) Amino acidposition 768 (e.g., E768Q, E768D) Amino acid position 769 (e.g., L769L)Amino acid position 770 (e.g., R770Q) Amino acid position 771 (e.g.,D771N) Amino acid position 777 (e.g., N777S) Amino acid position 778(e.g., V778I) Amino acid position 781 (e.g., Q781R) Amino acid position790 (e.g., L790F) Amino acid position 791 (e.g., Y791F) Amino acidposition 802 Amino acid position 804 (e.g., V804L, V804M, or V804E)(e.g., causing MTC) Amino acid position 805 (e.g., E805K) Amino acidposition 806 (e.g., E806C; Y806E, Y806F, Y806S, Y806G, Y806C²) Aminoacid position 818 (e.g., E818K) Amino acid position 819 (e.g., S819I)Amino acid position 823 (e.g., G823E) Amino acid position 826 (e.g.,Y826M)¹⁰ Amino acid position 833 (e.g., R833C) Amino acid position 841(e.g., P841L, P841P) Amino acid position 843 (e.g., E843D) Amino acidposition 844 (e.g., R844W, R844Q, R844L) Amino acid position 848 (e.g.,M848T) Amino acid position 852 (e.g., I852M) Amino acid position 866(e.g., A866W²) Amino acid position 873 (e.g., R873W) Amino acid position876 (e.g., A876V) Amino acid position 881 (e.g., L881V) Amino acidposition 882 Amino acid position 883 (e.g., A883F, A883S, A883T) Aminoacid position 884 (e.g., E884K) Amino acid position 886 (e.g., R886W)Amino acid position 891 (e.g., S891A) Amino acid position 897 (e.g.,R897Q) Amino acid position 898 (e.g., D898V) Amino acid position 901(e.g., E901K) Amino acid position 904 (e.g., S904F, S904C²) Amino acidposition 907 (e.g., K907E, K907M) Amino acid position 908 (e.g., R908K)Amino acid position 911 (e.g., G911D) Amino acid position 912 (e.g.,R912P, R912Q) Amino acid position 918 (e.g., M918T, M918V, M918L⁶)(e.g., causing MTC) Amino acid position 919 (e.g., A919V) Amino acidposition 921 (e.g., E921K) Amino acid position 922 (e.g., S922P, S922Y)Amino acid position 930 (e.g., T930M) Amino acid position 961 (e.g.,F961L) Amino acid position 972 (e.g., R972G) Amino acid position 982(e.g., R982C) Amino acid position 1009 (e.g., M1009V) Amino acidposition 1017 (e.g., D1017N) Amino acid position 1041 (e.g., V1041G)Amino acid position 1064 (e.g., M1064T) RET + 3¹ ¹U.S. patentapplication Publication No. 2014/0272951. ²Krampitz et al., Cancer 120:1920-1931, 2014. 3Latteyer, et al., J. Clin. Endocrinol. Metab. 101(3):1016-22, 2016. ⁴Silva, et al. Endocrine 49.2: 366-372, 2015. ⁵Scollo, etal., Endocr. J. 63(1): 87-91, 2016. ⁶Jovanovic, et al., Prilozi 36(1):93-107, 2015. ⁷Qi, et al., Oncotarget. 6(32): 33993-4003, 2015. *R525Wand A513D appear to act in combination with S891A to enchance oncogenicactivity. ⁸Kim, etal. ACTA ENDOCRINOLOGICA-BUCHAREST 11.2, 189-194,2015. ⁹Cecchirini, et al. Oncogene, 14, 2609-2612, 1997. ¹⁰Karrasch, etal. Eur. Thyroid J., 5(1): 73-7, 2016. ¹¹Scollo et al., Endocr. J. 63:87-91, 2016. ¹²Wells et al., Thyroid 25: 567-610, 2015.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes a splicevariation in a RET mRNA which results in an expressed protein that is analternatively spliced variant of RET having at least one residue deleted(as compared to the wild-type RET kinase) resulting in a constitutiveactivity of a RET kinase domain.

In some embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a RET gene that results in the production of a RETkinase that has one or more amino acid substitutions or insertions ordeletions in a RET gene that results in the production of a RET kinasethat has one or more amino acids inserted or removed, as compared to thewild-type RET kinase, which is more resistant to inhibition of itsphosphotransferase activity by one or more RET kinase inhibitor(s) thatis not a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof, as compared to a wildtype RET kinase or a RETkinase not including the same mutation. Such mutations can, optionally,not cause a cancer cell or a tumor to decrease its sensitivity totreatment with a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof (e.g., as compared to a cancer cellor a tumor that does not include the particular RET inhibitor resistancemutation). In such embodiments, a RET inhibitor resistance mutation canresult in a RET kinase that has one or more of an increased V_(max), adecreased K_(m) for ATP, and an increased K_(D) for a RET kinaseinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, when in thepresence of a RET kinase inhibitor that is not a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof, ascompared to a wildtype RET kinase or a RET kinase not having the samemutation in the presence of the same RET kinase inhibitor.

In other embodiments, the dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, includes at leastone point mutation in a RET gene that results in the production of a RETkinase that has one or more amino acid substitutions as compared to thewild-type RET kinase, and which has increased resistance to a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof, as compared to a wildtype RET kinase or a RET kinase notincluding the same mutation. In such embodiments, a RET inhibitorresistance mutation can result in a RET kinase that has one or more ofan increased V_(max), a decreased K_(m), and a decreased K_(D) in thepresence of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, as compared to a wildtype RET kinaseor a RET kinase not having the same mutation in the presence of the samecompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof.

Examples of RET inhibitor resistance mutations can, e.g., include pointmutations, insertions, or deletions in and near the ATP binding site inthe tertiary structure of RET kinase, including but not limited to thegatekeeper residue, P-loop residues, residues in or near the DFG motif,and ATP cleft solvent front amino acid residues. Additional examples ofthese types of mutations include changes in residues that may affectenzyme activity and/or drug binding including but are not limited toresidues in the activation loop, residues near or interacting with theactivation loop, residues contributing to active or inactive enzymeconformations, changes including mutations, deletions, and insertions inthe loop proceeding the C-helix and in the C-helix. Specific residues orresidue regions that may be changed (and are RET inhibitor resistancemutations) include but are not limited to those listed in Table 3 basedon the human wildtype RET protein sequence (e.g., SEQ ID NO: 1).Additional examples of RET inhibitor resistance mutation positions areshown in Table 4. Changes to these residues may include single ormultiple amino acid changes, insertions within or flanking thesequences, and deletions within or flanking the sequences.

In some embodiments, compounds of General Formula I and pharmaceuticallyacceptable salts and solvates are useful in treating patients thatdevelop cancers with RET inhibitor resistance mutations (that result inan increased resistance to a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, e.g., a substitution at amino acid position 804, e.g., V804M,V804L, or V804E) by either dosing in combination or as a follow-uptherapy to existing drug treatments (e.g., other RET kinase inhibitorsthat are not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof). Exemplary RET kinase inhibitors(e.g., other RET kinase inhibitors that are not a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof) aredescribed herein. In some embodiments, a RET kinase inhibitor can beselected from the group consisting of cabozantinib, vandetanib,alectinib, sorafenib, levatinib, ponatinib, dovitinib, sunitinib,foretinib, BLU667, and BLU6864.

In some embodiments, compounds of the General Formula I andpharmaceutically acceptable salts and solvates would be useful fortreating a cancer that has been identified as having one or more RETinhibitor resistance mutations (that result in an increased resistanceto a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E).

TABLE 3 RET Inhibitor Resistance Mutations Exemplary RET InhibitorResistance Mutations Amino acid position 804 (V804M, V804L,V804E)^(1, 2) Amino acid position 804/805 (V804M/E805K)³ Amino acidposition 806 (Y806C, Y806E)⁴ ¹Yoon et al., J. Med. Chem. 59(1): 358-73,2016. ²U.S. Pat. No. 8,629,135. ³Cranston, et al., Cancer Res. 66(20):10179-87, 2006. ⁴Carlomagno, et al., Endocr. Rel. Cancer 16(1): 233-41,2009.

TABLE 4 Additional Exemplary Amino Acid Positions of RET InhibitorResistance Mutations RET Residue # Kinase Location 788 CONTRIBUTES TOINACTIVE/ACTIVE CONFORMATION EQUILIBRIUM 804 GATEKEEPER 806 ATP CLEFTSOLVENT FRONT 810 SOLVENT FRONT 891 NEAR DFG MOTIF 729-739 P-LOOPRESIDUES 759-768 LOOP PROCEEDING C-HELIX 769-781 C-HELIX 868-874 NEAR ORINTERACTING WITH THE ACTIVATION LOOP 891-914 ACTIVATION LOOP

The oncogenic role of RET was firstly described in papillary thyroidcarcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63), which arisesfrom follicular thyroid cells and is the most common thyroid malignancy.Approximately 20-30% of PTC harbor somatic chromosomal rearrangements(translocations or inversions) linking the promoter and the 5′ portionsof constitutively expressed, unrelated genes to the RET tyrosine kinasedomain (Greco et al., Q. J. Nucl. Med. Mol. Imaging, 2009, 53, 440-54),therefore driving its ectopic expression in thyroid cells. To date, avariety of fusion partners have been identified, all providing aprotein/protein interaction domain that induces ligand-independent RETdimerization and constitutive kinase activity (see, e.g., Table 1). Therole of RET-PTC rearrangements in the pathogenesis of PTC has beenconfirmed in transgenic mice (Santoro et al., Oncogene, 1996, 12,1821-6). Recently, a 10.6 Mb pericentric inversion in chromosome 10,where RET gene maps, has been identified in about 2% of lungadenocarcinoma patients, generating different variants of the chimericgene KIF5B-RET (Ju et al., Genome Res., 2012, 22, 436-45; Kohno et al.,2012, Nature Med., 18, 375-7; Takeuchi et al., Nature Med., 2012, 18,378-81; Lipson et al., 2012, Nature Med., 18, 382-4). The fusiontranscripts are highly expressed and all the resulting chimeric proteinscontain the N-terminal portion of the coiled-coil region of KIF5B, whichmediates homodimerization, and the entire RET kinase domain. None of RETpositive patients harbor other known oncogenic alterations (such as EGFRor K-Ras mutation, ALK translocation), supporting the possibility thatKIF5B-RET fusion could be a driver mutation of lung adenocarcinoma. Theoncogenic potential of KIF5B-RET has been confirmed by transfecting thefusion gene into cultured cell lines: similarly to what has beenobserved with RET-PTC fusion proteins, KIF5B-RET is constitutivelyphosphorylated and induces NIH-3T3 transformation and IL-3 independentgrowth of BA-F3 cells. However, other RET fusion proteins have beenidentified in lung adenocarcinoma patients, such as the CCDC6-RET fusionprotein, which has been found to play a key role in the proliferation ofthe human lung adenocarcinoma cell line LC-2/ad (Journal of ThoracicOncology, 2012, 7(12): 1872-1876). RET inhibitors have been shown to beuseful in treating lung cancers involving RET rearrangements (Drilon, A.E. et al. J Clin Oncol 33, 2015 (suppl; abstr 8007)). RET fusionproteins have also been identified in patients having colorectal cancer(Song Eun-Kee, et al. International Journal of Cancer, 2015, 136:1967-1975).

Besides rearrangements of the RET sequence, gain of function pointmutations of RET proto-oncogene are also driving oncogenic events, asshown in medullary thyroid carcinoma (MTC), which arises fromparafollicular calcitonin-producing cells (de Groot, et al., EndocrineRev., 2006, 27, 535-60; Wells and Santoro, Clin. Cancer Res., 2009, 15,7119-7122). Around 25% of MTC are associated with multiple endocrineneoplasia type 2 (MEN2), a group of inherited cancer syndromes affectingneuroendocrine organs caused by germline activating point mutations ofRET. In MEN2 subtypes (MEN2A, MEN2B and Familial MTC/FMTC) RET genemutations have a strong phenotype-genotype correlation definingdifferent MTC aggressiveness and clinical manifestations of the disease.In MEN2A syndrome mutations involve one of the six cysteine residues(mainly C634) located in the cysteine-rich extracellular region, leadingto ligand-independent homodimerization and constitutive RET activation.Patients develop MTC at a young age (onset at 5-25 years) and may alsodevelop pheochromocytoma (50%) and hyperparathyroidism. MEN2B is mainlycaused by M918T mutation, which is located in the kinase domain. Thismutation constitutively activates RET in its monomeric state and alterssubstrate recognition by the kinase. MEN2B syndrome is characterized byan early onset (<1 year) and very aggressive form of MTC,pheochromocytoma (50% of patients) and ganglioneuromas. In FMTC the onlydisease manifestation is MTC, usually occurring at an adult age. Manydifferent mutations have been detected, spanning the entire RET gene.The remaining 75% of MTC cases are sporadic and about 50% of them harborRET somatic mutations: the most frequent mutation is M918T that, as inMEN2B, is associated with the most aggressive phenotype. Somatic pointmutations of RET have also been described in other tumors such ascolorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and smallcell lung carcinoma (Jpn. J. Cancer Res., 1995, 86, 1127-30).

RET signaling components have been found to be expressed in primarybreast tumors and to functionally interact with estrogen receptor-ccpathway in breast tumor cell lines (Boulay et al., Cancer Res. 2008, 68,3743-51; Plaza-Menacho et al., Oncogene, 2010, 29, 4648-57), while RETexpression and activation by GDNF family ligands could play an importantrole in perineural invasion by different types of cancer cells (Ito etal., Surgery, 2005, 138, 788-94; Gil et al., J. Natl. Cancer Inst.,2010, 102, 107-18; Iwahashi et al., Cancer, 2002, 94, 167-74).

RET is also expressed in 30-70% of invasive breast cancers, withexpression being relatively more frequent in estrogen receptor-positivetumors (Plaza-Menacho, I., et al., Oncogene, 2010, 29, 4648-4657;Esseghir, S., et al., Cancer Res., 2007, 67, 11732-11741; Morandi, A.,et al., Cancer Res., 2013, 73, 3783-3795; Gattelli, A., EMBO Mol. Med.,2013, 5, 1335-1350).

The identification of RET rearrangements has been reported in a subsetof (patient-derived xenograft) PDX established from colorectal cancer.Although the frequency of such event in colorectal cancer patientsremains to be defined, these data suggest a role of RET as a target inthis indication (Gozgit et al., AACR Annual Meeting 2014). Studies haveshown that the RET promoter is frequently methylated in colorectalcancers, and heterozygous missense mutations, which are predicted toreduce RET expression, are identified in 5-10% of cases, which suggeststhat RET might have some features of a tumor suppressor in sporadiccolon cancers (Luo, Y., et al., Oncogene, 2013, 32, 2037-2047; Sjoblom,T., et al., Science, 2006, 268-274; Cancer Genome Atlas Network, Nature,2012, 487, 330-337).

An increasing number of tumor types are now being shown to expresssubstantial levels of wild-type RET kinase that could have implicationsfor tumor progression and spread. RET is expressed in 50-65% ofpancreatic ductal carcinomas, and expression is more frequent inmetastatic and higher grade tumors (Ito, Y, et al., Surgery, 2005, 138,788-794; Zeng, Q., et al., J. Int. Med. Res. 2008, 36, 656-664).

In neoplasms of hematopoietic lineages, RET is expressed in acutemyeloid leukemia (AML) with monocytic differentiation, as well as inCMML (Gattei, V. et al., Blood, 1997, 89, 2925-2937; Gattei, V., et al.,Ann. Hematol, 1998, 77, 207-210; Camos, M., Cancer Res. 2006, 66,6947-6954). Recent studies have identified rare chromosomalrearrangements that involve RET in patients with chronic myelomonocyticleukemia (CMML). CMML is frequently associated with rearrangements ofseveral tyrosine kinases, which result in the expression of chimericcytosolic oncoproteins that lead to activation of RAS pathways(Kohlmann, A., et al., J. Clin. Oncol. 2010, 28, 2858-2865). In the caseof RET, gene fusions that link RET with BCR (BCR-RET) or with fibroblastgrowth factor receptor 1 oncogene partner (FGFR1OP-RET) weretransforming in early hematopoietic progenitor cells and could shiftmaturation of these cells towards monocytic paths, probably through theinitiation of RET-mediated RAS signaling (Ballerini, P., et al.,Leukemia, 2012, 26, 2384-2389).

RET expression has also been shown to occur in several other tumortypes, including prostate cancer, small-cell lung carcinoma, melanoma,renal cell carcinoma, and head and neck tumors (Narita, N., et al.,Oncogene, 2009, 28, 3058-3068; Mulligan, L. M., et al., GenesChromosomes Cancer, 1998, 21, 326-332; Flavin, R., et al., Urol. Oncol.,2012, 30, 900-905; Dawson, D. M., J Natl Cancer Inst, 1998, 90,519-523).

In neuroblastoma, RET expression and activation by GFLs has roles intumor cell differentiation, potentially collaborating with otherneurotrophic factor receptors to down regulate N-Myc, the expression ofwhich is a marker of poor prognosis (Hofstra, R. M., W., et al., Hum.Genet. 1996, 97, 362-364; Petersen, S. and Bogenmann, E., Oncogene,2004, 23, 213-225; Brodeur, G. M., Nature Ref Cancer, 2003, 3, 203-216).

Multitargeted inhibitors which cross react with RET are known (Borrello,M. G., et al., Expert Opin. Ther. Targets, 2013, 17(4), 403-419;International Patent Application Nos. WO 2014/141187, WO 2014/184069,and WO 2015/079251).

Accordingly, provided herein are methods for treating a patientdiagnosed with (or identified as having) a cancer (e.g., aRET-associated cancer) (e.g., a RET-associated cancer that includes oneor more RET inhibitor resistance mutations) that include administeringto the patient a therapeutically effective amount of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof. Also provided herein are methods for treating a patientidentified or diagnosed as having a RET-associated cancer (e.g., apatient that has been identified or diagnosed as having a RET-associatedcancer through the use of a regulatory agency-approved, e.g.,FDA-approved test or assay for identifying dysregulation of a RET gene,a RET kinase, or expression or activity or level of any of the same, ina patient or a biopsy sample from the patient) (e.g., any of theRET-associated cancers described herein or known in the art) (e.g., aRET-associated cancer that includes one or more RET inhibitor resistancemutations) that include administering to the patient a therapeuticallyeffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof. In some embodiments, the test or assay is providedas a kit.

Also provided are methods for treating cancer in a patient in needthereof, the method comprising: (a) determining if the cancer in thepatient is a RET-associated cancer (e.g., a RET-associated cancerincluding RET-associated cancers having one or more RET inhibitorresistance mutations) (e.g., using a regulatory-agency approved, e.g.,FDA-approved, kit for identifying dysregulation of a RET gene, a RETkinase, or expression or activity or level of any of the same, in apatient or a biopsy sample from the patient, or by performing any of thenon-limiting examples of assays described herein); and (b) if the canceris determined to be a RET-associated cancer, administering to thepatient a therapeutically effective amount of a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof or apharmaceutical composition thereof. Some embodiments of these methodsfurther include administering to the subject another anticancer agent(e.g., another RET inhibitor, e.g., a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a different RET inhibitor that is a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof). In some embodiments, the subject was previously treated with aRET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or previouslytreated with another anticancer treatment, e.g., after resection of atumor or radiation therapy.

Also provided are methods of treating a patient (e.g., a patientsuspected of having a RET-associated cancer, a patient presenting withone or more symptoms of a RET-associated cancer, or a patient having anelevated risk of developing a RET-associated cancer) that includeperforming an assay (e.g., an assay that utilizes next generationsequencing, pyrosequencing, immunohistochemistry, or break apart FISHanalysis) (e.g., using a regulatory agency-approved, e.g., FDA-approvedkit) on a sample obtained from the patient to determine whether thepatient has dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same (e.g., one or more RET inhibitorresistance mutations), and administering (e.g., specifically orselectively administering) a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof or a pharmaceutical composition thereof to the patientdetermined to have dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same. Additional,non-limiting assays that may be used in these methods are describedherein. Additional assays are also known in the art. Some embodiments ofthese methods further include administering to the subject anotheranticancer agent (e.g., another RET inhibitor, e.g., a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a different RET inhibitor that isa compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof). In some embodiments of these methods, the subject waspreviously treated with a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof or previously treated with another anticancer treatment, e.g.,after resection of a tumor or radiation therapy.

Also provided is a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof for use in treating a RET-associated cancer (e.g., aRET-associated cancer including RET-associated cancers having one ormore RET inhibitor resistance mutations) in a patient identified ordiagnosed as having a RET-associated cancer through a step of performingan assay (e.g., an in vitro assay) (e.g., an assay that utilizes nextgeneration sequencing, immunohistochemistry, or break apart FISHanalysis) (e.g., using a regulatory agency-approved, e.g., FDA-approvedkit) on a sample obtained from the patient to determine whether thepatient has dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same (e.g., one or more RET inhibitorresistance mutations), where the presence of dysregulation of a RETgene, a RET kinase, or expression or activity or level of any of thesame, identifies that the patient has a RET-associated cancer. Alsoprovided is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament for treating a RET-associated cancer (e.g., aRET-associated cancer having one or more RET inhibitor resistancemutations) in a patient identified or diagnosed as having aRET-associated cancer through a step of performing an assay (e.g., an invitro assay) (e.g., an assay that utilizes next generation sequencing,immunohistochemistry, or break apart FISH analysis) (e.g., using aregulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the patient to determine whether the patient has adysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same where the presence of dysregulation of a RETgene, a RET kinase, or expression or activity or level of any of thesame, identifies that the patient has a RET-associated cancer. Someembodiments of any of the methods or uses described herein furtherinclude recording in the patient's clinical record (e.g., a computerreadable medium) that the patient determined to have dysregulation of aRET gene, a RET kinase, or expression or activity or level of any of thesame (e.g., determined to have one or more RET inhibitor resistancemutations), through the performance of the assay, should be administereda compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof or a pharmaceutical composition thereof.

Also provided is a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of a cancer(e.g., a RET-associated cancer, e.g., a RET-associated cancer having oneor more RET inhibitor resistance mutations) in a patient in need thereofor a patient identified or diagnosed as having a RET-associated cancer(e.g., a patient that has been identified or diagnosed as having aRET-associated cancer through the use of a regulatory agency-approved,e.g., FDA-approved, kit for identifying dysregulation of a RET gene, aRET kinase, or expression or activity or level of any of the same, in apatient or a biopsy sample from the sample) (e.g., any of theRET-associated cancers described herein or known in the art). Alsoprovided is the use of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament for treating a cancer (e.g., a RET-associated cancer,e.g., a RET-associated cancer having one or more RET inhibitorresistance mutations) in a patient identified or diagnosed as having aRET-associated cancer (e.g., a patient that has been identified ordiagnosed as having a RET-associated cancer through the use of aregulatory agency-approved, e.g., FDA-approved, kit for identifyingdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, in a patient or a biopsy sample from thepatient) (e.g., any of the RET-associated cancers described herein orknown in the art).

In some embodiments of any of the methods or uses described herein, thepatient has been identified or diagnosed as having a cancer withdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same (e.g., a cancer having one or more RETinhibitor resistance mutations) (e.g., as determined using a regulatoryagency-approved, e.g., FDA-approved, assay or kit). In some embodimentsof any of the methods or uses described herein, the patient has a tumorthat is positive for dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., a tumorpositive for one or more RET inhibitor resistance mutations) (e.g., asdetermined using a regulatory-agency-approved assay or kit). In someembodiments of any of the methods or uses described herein, the patientcan be a patient with a tumor(s) that is positive for dysregulation of aRET gene, a RET kinase, or expression or activity or level of any of thesame (e.g., a tumor that is positive for one or more RET inhibitorresistance mutations) (e.g., identified as positive using a regulatoryagency-approved, e.g., FDA-approved, assay or kit). In some embodimentsof any of the methods or uses described herein, the patient can be apatient whose tumors have dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., a patientwhose tumors have one or more RET inhibitor resistance mutations) (e.g.,where the tumor is identified as such using a regulatoryagency-approved, e.g., FDA-approved, kit or assay). In some embodimentsof any of the methods or uses described herein, the patient is suspectedof having a RET-associated cancer. In some embodiments of any of themethods or uses described herein, the patient has a clinical recordindicating that the patient has a tumor that has dysregulation of a RETgene, a RET kinase, or expression or activity or level of any of thesame (e.g., a tumor having one or more RET inhibitor resistancemutations) (and optionally the clinical record indicates that thepatient should be treated with any of the compounds of General Formula Ior a pharmaceutically acceptable salts or solvates thereof orcompositions provided herein).

Also provided are methods of treating a patient that includeadministering a therapeutically effective amount of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof to a patient having a clinical record that indicates that thepatient has dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same (e.g., one or more RET inhibitorresistance mutations). Also provided is the use of a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof forthe manufacture of a medicament for treating a RET-associated cancer ina patient having a clinical record that indicates that the patient hasdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same (e.g., one or more RET inhibitor resistancemutations). Also provided is the use of a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof for treating aRET-associated cancer in a patient having a clinical record thatindicates that the patient has dysregulation of a RET gene, a RETkinase, or expression or activity or level of any of the same (e.g., oneor more RET inhibitor resistance mutations). Some embodiments of thesemethods and uses can further include: a step of performing an assay(e.g., an in vitro assay) (e.g., an assay that utilizes next generationsequencing, immunohistochemistry, or break apart FISH analysis) (e.g.,using a regulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the patient to determine whether the patient hasdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, and recording the information in a patient'sclinical file (e.g., a computer readable medium) that the patient hasbeen identified to have dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., one or moreRET inhibitor resistance mutations).

Also provided herein is a method of treating a subject. The methodincludes performing an assay on a sample obtained from the subject todetermine whether the subject has dysregulation of a RET gene, a RETprotein, or expression or level of any of the same (e.g., one or moreRET inhibitor resistance mutations). The method also includesadministering to a subject determined to have dysregulation of a RETgene, a RET protein, or expression or activity, or level of any of thesame (e.g., one or more RET inhibitor resistance mutations) atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the RET fusion can be selected from a KIF5B-RET fusion anda CCDC6-RET fusion. In some embodiments, the dysregulation in a RETgene, a RET kinase protein, or expression or activity of the same is agene or chromosome translocation that results in the expression of a RETfusion protein (e.g., any of the RET fusion proteins described herein).In some embodiments, the dysregulation in a RET gene, a RET kinaseprotein, or expression or activity or level of any of the same is one ormore point mutation in the RET gene (e.g., any of the one or more of theRET point mutations described herein). The one or more point mutationsin a RET gene can result, e.g., in the translation of a RET proteinhaving one or more of the following amino acid substitutions: M918T,M918V, C634W, V804L, and V804M. In some embodiments, the dysregulationin a RET gene, a RET kinase protein, or expression or activity or levelof any of the same is one or more RET inhibitor resistance mutations(e.g., any combination of the one or more RET inhibitor resistancemutations described herein). Some embodiments of these methods furtherinclude administering to the subject another anticancer agent (e.g.,another RET inhibitor, e.g., a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, or a different RET inhibitor that is a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof).

Also provided are methods (e.g., in vitro methods) of selecting atreatment for a patient that includes administration of atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof for a patientidentified or diagnosed as having a RET-associated cancer (e.g., aRET-associated cancer having one or more RET inhibitor resistancemutations) (e.g., a patient that has been identified or diagnosed ashaving a RET-associated cancer through the use of a regulatoryagency-approved, e.g., FDA-approved, kit for identifying dysregulationof a RET gene, a RET kinase, or expression or activity or level of anyof the same, in a patient or a biopsy sample from the patient) (e.g.,any of the RET-associated cancers described herein or known in the art).Some embodiments can further include administering the selectedtreatment to the patient identified or diagnosed as having aRET-associated cancer (e.g., a RET-associated cancer having one or moreRET inhibitor resistance mutations). Some embodiments can furtherinclude administering the selected treatment to the patient identifiedor diagnosed as having a RET-associated cancer (e.g., a RET-associatedcancer having one or more RET inhibitor resistance mutations). Someembodiments can further include a step of performing an assay (e.g., anin vitro assay) (e.g., an assay that utilizes the next generationsequencing, immunohistochemistry, or break apart FISH analysis) (e.g.,using a regulatory agency-approved, e.g., FDA-approved, kit) on a sampleobtained from the patient to determine whether the patient hasdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same (e.g., one or more RET inhibitor resistancemutations), and identifying and diagnosing a patient determined to havedysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same (e.g., one or more RET inhibitor resistancemutations), as having a RET-associated cancer.

Also provided herein are methods of selecting a treatment for a patientthat include administration of a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, wherein the methods include a step of performing anassay (e.g., an in vitro assay) (e.g., an assay that utilizes nextgeneration sequencing, immunohistochemistry, or break apart FISHanalysis) (e.g., using a regulatory agency-approved, e.g., FDA-approved,kit) on a sample obtained from the patient to determine whether thepatient has dysregulation of a RET gene, a RET kinase, or expression oractivity or level of any of the same (e.g., one or more RET inhibitorresistance mutations), and identifying or diagnosing a patientdetermined to have dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., one or moreRET inhibitor resistance mutations), as having a RET-associated cancer,and selecting a therapeutic treatment including administration of atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof to the patientidentified or diagnosed as having a RET-associated cancer. Someembodiments further include administering the selected treatment to thepatient identified or diagnosed as having a RET-associated cancer.

Also provided are methods of selecting a patient for treatment includingadministration of a therapeutically effective amount of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof or a pharmaceutical composition thereof, wherein the methodsinclude selecting, identifying, or diagnosing a patient having aRET-associated cancer (e.g., a RET-associated cancer having one or moreRET inhibitor resistance mutations), and selecting the patient fortreatment including administration of a therapeutically-effective amountof a compound of General Formula I or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, identifying or diagnosing apatient as having a RET-associated cancer can include a step ofperforming an assay (e.g., an in vitro assay) (e.g., an assay thatutilizes next generation sequencing, immunohistochemistry, or breakapart FISH analysis) (e.g., using a regulatory agency-approved, e.g.,FDA-approved, kit) on a sample obtained from the patient to determinewhether the patient has dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same (e.g., one or moreRET inhibitor resistance mutations), and identifying or diagnosing apatient determined to have dysregulation of a RET gene, a RET kinase, orexpression or activity or level of any of the same, as having aRET-associated cancer. In some embodiments, the method of selecting atreatment can be used as a part of a clinical study that includesadministration of various treatments of a RET-associated cancer.

In some embodiments of any of the methods or uses described herein, anassay used to determine whether the patient has dysregulation of a RETgene, or a RET kinase, or expression or activity or level of any of thesame (e.g., one or more RET inhibitor resistance mutations), using asample (e.g., a biological sample or a biopsy sample (e.g., aparaffin-embedded biopsy sample) from a patient (e.g., a patientsuspected of having a RET-associated cancer, a patient having one ormore symptoms of a RET-associated cancer, and/or a patient that has anincreased risk of developing a RET-associated cancer) can include, forexample, next generation sequencing, immunohistochemistry, fluorescencemicroscopy, break apart FISH analysis, Southern blotting, Westernblotting, FACS analysis, Northern blotting, and PCR-based amplification(e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known inthe art, the assays are typically performed, e.g., with at least onelabelled nucleic acid probe or at least one labelled antibody orantigen-binding fragment thereof. Assays can utilize other detectionmethods known in the art for detecting dysregulation of a RET gene, aRET kinase, or expression or activity or levels of any of the same (see,e.g., the references cited herein).

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment or therapy in addition to compositions provided herein may be,for example, surgery, radiotherapy, and chemotherapeutic agents, such askinase inhibitors, signal transduction inhibitors and/or monoclonalantibodies. Compounds of General Formula I therefore may also be usefulas adjuvants to cancer treatment, that is, they can be used incombination with one or more additional therapies or therapeutic agents,for example a chemotherapeutic agent that works by the same or by adifferent mechanism of action.

In some embodiments of any the methods described herein, the compound ofGeneral Formula I (or a pharmaceutically acceptable salt or solvatethereof) is administered in combination with a therapeutically effectiveamount of at least one additional therapeutic agent selected from one ormore additional therapies or therapeutic (e.g., chemotherapeutic)agents.

Non-limiting examples of additional therapeutic agents include: otherRET-targeted therapeutic agents (i.e. other RET kinase inhibitors; RETinhibitors that are not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof), receptor tyrosinekinase-targeted therapeutic agents, signal transduction pathwayinhibitors, checkpoint inhibitors, modulators of the apoptosis pathway(e.g. obataclax); cytotoxic chemotherapeutics, angiogenesis-targetedtherapies, immune-targeted agents, and radiotherapy.

In some embodiments, the other RET-targeted therapeutic is a multikinaseinhibitor exhibiting RET inhibition activity. In some embodiments, theother RET-targeted therapeutic inhibitor is selective for a RET kinase.Exemplary RET-targeted therapeutics can exhibit inhibition activity(IC₅₀) against a RET kinase of less than about 1000 nM, less than about500 nM, less than about 200 nM, less than about 100 nM, less than about50 nM, less than about 25 nM, less than about 10 nM, or less than about1 nM.

Non-limiting examples of RET-targeted therapeutic agents includealectinib, apatinib, cabozantinib (XL-184), dovitinib, lenvatinib,motesanib, nintedanib, ponatinib, regorafenib, sitravatinib (MGCD516),sunitinib, sorafenib, vatalanib, vandetanib, AUY-922(5-(2,4-Dihydroxy-5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide),BLU6864, BLU-667, DCC-2157, NVP-AST487(1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea),PZ-1, RPI-1(1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one),RXDX-105(1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea),SPP86(1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), andTG101209(N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]-benzenesulfonamide).

Additional examples of other RET kinase inhibitors include thosedescribed in U.S. Pat. Nos. 9,150,517 and 9,149,464, and InternationalPublication No. WO 2014075035, all of which are hereby incorporated byreference. For example, in some embodiments the other RET inhibitor is acompound of formula I:

wherein R₁ is C6-C24alkyl or polyethylene glycol; or a pharmaceuticallyacceptable alt form thereof. In some embodiments, the other RETinhibitor is4-{5-[bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyricacid dodecyl ester.

Yet other therapeutic agents include RET inhibitors such as thosedescribed, for example, in U.S. Pat. Nos. 7,504,509; 8,299,057;8,399,442; 8,067,434; 8,937,071; 9,006,256; and 9,035,063; U.S.Publication Nos. 2014/0121239; 20160176865; 2011/0053934; 2011/0301157;2010/0324065; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195;International Publication Nos. WO 2014/184069; WO 2014/072220; WO2012/053606; WO 2009/017838; WO 2008/031551; WO 2007/136103; WO2007/087245; WO 2007/057399; WO 2005/051366; WO 2005/062795; and WO2005/044835; and J. Med. Chem. 2012, 55 (10), 4872-4876, all of whichare hereby incorporated by reference in their entireties.

Non-limiting examples of receptor tyrosine kinase (Trk) targetedtherapeutic agents, include afatinib, cabozantinib, cetuximab,crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab,sunitinib, trastuzumab, 1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea,AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Gö 6976,GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101,TPX-0005, and TSR-011. Additional Trk targeted therapeutic agentsinclude those described in U.S. Pat. Nos. 8,450,322; 8,513,263;8,933,084; 8,791,123; 8,946,226; 8,450,322; 8,299,057; and 8,912,194;U.S. Publication No. 2016/0137654; 2015/0166564; 2015/0051222;2015/0283132; and 2015/0306086; International Publication No. WO2010/033941; WO 2010/048314; WO 2016/077841; WO 2011/146336; WO2011/006074; WO 2010/033941; WO 2012/158413; WO 2014078454; WO2014078417; WO 2014078408; WO 2014078378; WO 2014078372; WO 2014078331;WO 2014078328; WO 2014078325; WO 2014078323; WO 2014078322; WO2015175788; WO 2009/013126; WO 2013/174876; WO 2015/124697; WO2010/058006; WO 2015/017533; WO 2015/112806; WO 2013/183578; and WO2013/074518, all of which are hereby incorporated by reference in theirentireties.

Further examples of Trk inhibitors can be found in U.S. Pat. No.8,637,516, International Publication No. WO 2012/034091, U.S. Pat. No.9,102,671, International Publication No. WO 2012/116217, U.S.Publication No. 2010/0297115, International Publication No. WO2009/053442, U.S. Pat. No. 8,642,035, International Publication No. WO2009092049, U.S. Pat. No. 8,691,221, International Publication No.WO2006131952, all of which are incorporated by reference in theirentireties herein. Exemplary Trk inhibitors include GNF-4256, describedin Cancer Chemother. Pharmacol. 75(1):131-141, 2015; and GNF-5837(N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]-urea),described in ACS Med. Chem. Lett. 3(2): 140-145, 2012, each of which isincorporated by reference in its entirety herein.

Additional examples of Trk inhibitors include those disclosed in U.S.Publication No. 2010/0152219, U.S. Pat. No. 8,114,989, and InternationalPublication No. WO 2006/123113, all of which are incorporated byreference in their entireties herein. Exemplary Trk inhibitors includeAZ623, described in Cancer 117(6):1321-1391, 2011; AZD6918, described inCancer Biol. Ther. 16(3):477-483, 2015; AZ64, described in CancerChemother. Pharmacol. 70:477-486, 2012; AZ-23((S)-5-Chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine),described in Mol. Cancer Ther. 8:1818-1827, 2009; and AZD7451; each ofwhich is incorporated by reference in its entirety.

A Trk inhibitor can include those described in U.S. Pat. Nos. 7,615,383;7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; 5,877,016; and5,844,092, each of which is incorporated by reference in its entirety.

Further examples of Trk inhibitors include CEP-751, described in Int. J.Cancer 72:672-679, 1997; CT327, described in Acta Derm. Venereol.95:542-548, 2015; compounds described in International Publication No.WO 2012/034095; compounds described in U.S. Pat. No. 8,673,347 andInternational Publication No. WO 2007/022999; compounds described inU.S. Pat. No. 8,338,417; compounds described in InternationalPublication No. WO 2016/027754; compounds described in U.S. Pat. No.9,242,977; compounds described in U.S. Publication No. 2016/0000783;sunitinib(N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide),as described in PLoS One 9:e95628, 2014; compounds described inInternational Publication No. WO 2011/133637; compounds described inU.S. Pat. No. 8,637,256; compounds described in Expert. Opin. Ther. Pat.24(7):731-744, 2014; compounds described in Expert Opin. Ther. Pat.19(3):305-319, 2009; (R)-2-phenylpyrrolidine substitutedimadizopyridazines, e.g.,(4-((5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanoneas described in ACS Med. Chem. Lett. 6(5):562-567, 2015; GTx-186 andothers, as described in PLoS One 8(12):e83380, 2013; K252a((9S-(9a,10J3,12a))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one),as described in Mol. Cell Biochem. 339(1-2):201-213, 2010;4-aminopyrazolylpyrimidines, e.g., AZ-23(((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine)),as described in J. Med. Chem. 51(15):4672-4684, 2008; PHA-739358(danusertib), as described in Mol. Cancer Ther. 6:3158, 2007; Go 6976(5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile),as described in J. Neurochem. 72:919-924, 1999; GW441756((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one),as described in IJAE 115:117, 2010; milciclib (PHA-848125AC), describedin J. Carcinog. 12:22, 2013; AG-879((2E)-3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide);altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);cabozantinib(N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);lestaurtinib((5S,6S,8R)-6-Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-13(6H)-one);dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);ONO-5390556; regorafenib(4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamidehydrate); VSR-902A; all of the references above are incorporated byreference in their entireties herein.

The ability of a Trk inhibitor to act as a TrkA, TrkB, and/or Trk Cinhibitor may be tested using the assays described in Examples A and Bin U.S. Pat. No. 8,513,263, which is incorporated herein by reference.

In some embodiments, signal transduction pathway inhibitors includeRas-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib,encorafinib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6Kpathway inhibitors (e.g. everolimus, rapamycin, perifosine,temsirolimus), and other kinase inhibitors, such as baricitinib,brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin,regorafenib, ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110,INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088,NMS-1286937, PF 477736((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1Hpyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide),PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106,RXDX108, and TG101209(N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide).

Non-limiting examples of checkpoint inhibitors include ipilimumab,tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C,BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, andpembrolizumab.

In some embodiments, cytotoxic chemotherapeutics are selected fromarsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin,cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin,docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine,irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin,paclitaxel, pemetrexed, temozolomide, and vincristine.

Non-limiting examples of angiogenesis-targeted therapies includeaflibercept and bevacizumab.

In some embodiments, immune-targeted agents are selected fromaldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab,prednisone, and sipuleucel-T.

Non-limiting examples of radiotherapy include radioiodide therapy,external-beam radiation, and radium 223 therapy.

Additional kinase inhibitors include those described in, for example,U.S. Pat. Nos. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002;8,815,901; 8,912,204; 9,260,437; 9,273,051; U.S. Publication No. US2015/0018336; International Publication No. WO 2007/002325; WO2007/002433; WO 2008/080001; WO 2008/079906; WO 2008/079903; WO2008/079909; WO 2008/080015; WO 2009/012283; WO 2009/143018; WO2009/143024; WO 2009/152083; WO 2010/111527; WO 2012/109075; WO2014/194127; WO 2015/112806; WO 2007/110344; WO 2009/071480; WO2009/118411; WO 2010/031816; WO 2010/145998; WO 2011/092120; WO2012/101032; WO 2012/139930; WO 2012/143248; WO 2012/152763; WO2013/014039; WO 2013/102059; WO 2013/050448; WO 2013/050446; WO2014/019908; WO 2014/072220; WO 2014/184069; and WO 2016/075224 all ofwhich are hereby incorporated by reference in their entireties.

Further examples of kinase inhibitors include those described in, forexample, WO 2016/081450; WO 2016/022569; WO 2016/011141; WO 2016/011144;WO 2016/011147; WO 2015/191667; WO 2012/101029; WO 2012/113774; WO2015/191666; WO 2015/161277; WO 2015/161274; WO 2015/108992; WO2015/061572; WO 2015/058129; WO 2015/057873; WO 2015/017528;WO/2015/017533; WO 2014/160521; and WO 2014/011900, each of which ishereby incorporated by reference in its entirety.

Accordingly, also provided herein is a method of treating cancer,comprising administering to a patient in need thereof a pharmaceuticalcombination for treating cancer which comprises (a) a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, (b) an additional therapeutic agent, and (c) optionally atleast one pharmaceutically acceptable carrier for simultaneous, separateor sequential use for the treatment of cancer, wherein the amounts ofthe compound of General Formula I or a pharmaceutically acceptable saltor solvate thereof and the additional therapeutic agent are togethereffective in treating the cancer.

In some embodiments, the additional therapeutic agent(s) includes anyone of the above listed therapies or therapeutic agents which arestandards of care in cancers wherein the cancer has a dysregulation of aRET gene, a RET protein, or expression or activity, or level of any ofthe same.

These additional therapeutic agents may be administered with one or moredoses of the compound of General Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, or pharmaceutical compositionthereof, as part of the same or separate dosage forms, via the same ordifferent routes of administration, and/or on the same or differentadministration schedules according to standard pharmaceutical practiceknown to one skilled in the art.

Also provided herein is (i) a pharmaceutical combination for treating acancer (e.g., a RET-associated cancer (e.g., a RET-associated cancerhaving one or more RET inhibitor resistance mutations)) in a patient inneed thereof, which comprises (a) a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, (b) at least oneadditional therapeutic agent (e.g., any of the exemplary additionaltherapeutic agents described herein or known in the art), and (c)optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of cancer,wherein the amounts of the compound of General Formula I orpharmaceutically acceptable salt or solvate thereof and of theadditional therapeutic agent are together effective in treating thecancer; (ii) a pharmaceutical composition comprising such a combination;(iii) the use of such a combination for the preparation of a medicamentfor the treatment of cancer; and (iv) a commercial package or productcomprising such a combination as a combined preparation forsimultaneous, separate or sequential use; and to a method of treatmentof cancer a patient in need thereof. In one embodiment the patient is ahuman.

The term “pharmaceutical combination”, as used herein, refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof and at least one additionaltherapeutic agent (e.g., a chemotherapeutic agent), are bothadministered to a patient simultaneously in the form of a singlecomposition or dosage. The term “non-fixed combination” means that acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof and at least one additional therapeutic agent (e.g.,chemotherapeutic agent) are formulated as separate compositions ordosages such that they may be administered to a patient in need thereofsimultaneously, concurrently or sequentially with variable interveningtime limits, wherein such administration provides effective levels ofthe two or more compounds in the body of the patient. These also applyto cocktail therapies, e.g. the administration of three or more activeingredients

Accordingly, also provided herein is a method of treating a cancer(e.g., a RET-associated cancer (e.g., a RET-associated cancer having oneor more RET inhibitor resistance mutations)), comprising administeringto a patient in need thereof a pharmaceutical combination for treatingcancer which comprises (a) a compound of General Formula I orpharmaceutically acceptable salt or solvate thereof, (b) an additionaltherapeutic agent, and (c) optionally at least one pharmaceuticallyacceptable carrier for simultaneous, separate or sequential use for thetreatment of cancer, wherein the amounts of the compound of GeneralFormula I or pharmaceutically acceptable salt or solvate thereof and theadditional therapeutic agent are together effective in treating thecancer. In one embodiment, the compound of General Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as separate dosages.In one embodiment, the compound of General Formula I or pharmaceuticallyacceptable salt or solvate thereof, and the additional therapeutic agentare administered as separate dosages sequentially in any order, injointly therapeutically effective amounts, e.g. in daily orintermittently dosages. In one embodiment, compound of General Formula Ior pharmaceutically acceptable salt or solvate thereof, and theadditional therapeutic agent are administered simultaneously as acombined dosage.

Also provided herein is a method of treating a disease or disordermediated by RET (e.g., dysregulation of RET gene, a RET kinase, orexpression or activity or level of any of the same, e.g., one or moreRET inhibitor resistance mutations) in a patient in need of suchtreatment, the method comprising administering to the patient atherapeutically effective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof or a pharmaceuticalcomposition thereof. A disease or disorder mediated by RET (e.g.,dysregulation of RET gene, a RET kinase, or expression or activity orlevel of any of the same, e.g., one or more RET inhibitor resistancemutations) can include any disease, disorder or condition that isdirectly or indirectly linked to expression or activity of RET,including overexpression and/or abnormal activity levels. In oneembodiment, the disease is cancer (e.g., a RET-associated cancer). Inone embodiment, the cancer is any of the cancers or RET-associatedcancers described herein.

Although the genetic basis of tumorigenesis may vary between differentcancer types, the cellular and molecular mechanisms required formetastasis appear to be similar for all solid tumor types. During ametastatic cascade, the cancer cells lose growth inhibitory response,undergo alterations in adhesiveness and produce enzymes that can degradeextracellular matrix components. This leads to detachment of tumor cellsfrom the original tumor, infiltration into the circulation through newlyformed vasculature, migration and extravasation of the tumor cells atfavorable distant sites where they may form colonies. A number of geneshave been identified as being promoters or suppressors of metastasis.For example, overexpression of glial cell-derived neurotrophic factor(GDNF) and its RET receptor tyrosine kinase have been correlated withcancer proliferation and metastasis. See, e.g., Zeng, Q. et al. J. Int.Med. Res. (2008) 36(4): 656-64.

Accordingly, also provided herein are methods for inhibiting,preventing, aiding in the prevention, or decreasing the symptoms ofmetastasis of a cancer in a patient in need thereof, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositionthereof. Such methods can be used in the treatment of one or more of thecancers described herein. See, e.g., US Publication No. 2013/0029925;International Publication No. WO 2014/083567; and U.S. Pat. No.8,568,998. In some embodiments, the cancer is a RET-associated cancer.In some embodiments, the compound of General Formula I or apharmaceutically acceptable salt or solvate thereof is used incombination with an additional therapy or another therapeutic agent,including a chemotherapeutic agent, such as a kinase inhibitor.

The term “metastasis” is an art known term and means the formation of anadditional tumor (e.g., a solid tumor) at a site distant from a primarytumor in a subject or patient, where the additional tumor includes thesame or similar cancer cells as the primary tumor.

Also provided are methods of decreasing the risk of developing ametastasis or an additional metastasis in a patient having aRET-associated cancer (e.g., a RET-associated cancer having one or moreRET inhibitor resistance mutations) that include: selecting,identifying, or diagnosing a patient as having a RET-associated cancer(e.g., a RET-associated cancer having one or more RET inhibitorresistance mutations), and administering a therapeutically effectiveamount of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof to the patient selected, identified,or diagnosed as having a RET-associated cancer. Also provided aremethods of decreasing the risk of developing a metastasis or anadditional metastasis in a patient having a RET-associated cancer (e.g.,a RET-associated cancer having one or more RET inhibitor resistancemutations) that includes administering a therapeutically effectiveamount of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvent thereof to a patient having a RET-associatedcancer. The decrease in the risk of developing a metastasis or anadditional metastasis in a patient having a RET-associated cancer can becompared to the risk of developing a metastasis or an additionalmetastasis in the patient prior to treatment, or as compared to apatient or a population of patients having a similar or the sameRET-associated cancer that has received no treatment or a differenttreatment.

The phrase “risk of developing a metastasis” means the risk that asubject or patient having a primary tumor will develop an additionaltumor (e.g., a solid tumor) at a site distant from a primary tumor in asubject or patient over a set period of time, where the additional tumorincludes the same or similar cancer cells as the primary tumor. Methodsfor reducing the risk of developing a metastasis in a subject or patienthaving a cancer are described herein.

The phrase “risk of developing additional metastases” means the riskthat a subject or patient having a primary tumor and one or moreadditional tumors at sites distant from the primary tumor (where the oneor more additional tumors include the same or similar cancer cells asthe primary tumor) will develop one or more further tumors distant fromthe primary tumor, where the further tumors include the same or similarcancer cells as the primary tumor. Methods for reducing the risk ofdeveloping additional metastasis are described herein.

In some embodiments, the presence of one or more RET inhibitorresistance mutations in a tumor causes the tumor to be more resistant totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof (e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E).Methods useful when a RET inhibitor resistance mutation causes the tumorto be more resistant to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof are described below. For example, provided herein aremethods of treating a subject having a cancer that include: identifyinga subject having a cancer cell that has one or more RET inhibitorresistance mutations (that confer increased resistance to a cancer cellor tumor to treatment with a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, e.g., a substitution at amino acid position 804, e.g., V804M,V804L, or V804E); and administering to the identified subject atreatment that does not include a RET inhibitor that is not a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy (e.g., a treatment that includes a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof). Also provided are methods of treating a subject identified ashaving a cancer cell that has one or more RET inhibitor resistancemutations (that confer increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E)that include administering to the subject a treatment that does notinclude a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy(e.g., a treatment that includes a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof). Also provided aremethods of selecting a treatment for a subject having a cancer thatinclude: identifying a subject having a cancer cell that has one or moreRET inhibitor resistance mutations (that confer increased resistance toa cancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E); and selecting a treatment that does not includea RET inhibitors that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy forthe identified subject (e.g., a treatment that includes a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof). Also provided are methods of selecting a treatment for asubject having a cancer that include: selecting a treatment that doesnot include a RET inhibitor that is not a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof as amonotherapy (e.g., a treatment that includes a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof) fora subject identified as having a cancer cell that has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E). Also provided are methods of selecting asubject having a cancer for a treatment that does not include a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapythat include: identifying a subject having a cancer cell that has one ormore RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, e.g., a substitution at amino acidposition 804, e.g., V804M, V804L, or V804E); and selecting theidentified subject for a treatment that does not include a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy (e.g., a treatmentthat includes a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof). Also provided are methods ofselecting a subject having a cancer for a treatment that does notinclude a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapythat include: selecting a subject identified as having a cancer cellthat has one or more RET inhibitor resistance mutations (that conferincreased resistance to a cancer cell or tumor to treatment with a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E),for a treatment that does not include a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy (e.g., a treatment that includes acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof). Also provided are methods of determining thelikelihood that a subject having a cancer will have a positive responseto treatment with a RET inhibitor that is not a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy that include: determining whether a cancer cell in a sampleobtained from the subject has one or more RET inhibitor resistancemutations (that confer increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);and determining that a subject having a cancer cell that has one or moreRET inhibitor resistance mutations (that confer increased resistance toa cancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E), has a decreased likelihood of having a positiveresponse to treatment with a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy. Also provided are methods of determining thelikelihood that a subject having cancer will have a positive response totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof as amonotherapy that include: determining that a subject having a cancercell that has one or more RET inhibitor resistance mutations (thatconfer increased resistance to a cancer cell or tumor to treatment witha RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E),has a decreased likelihood of having a positive response to treatmentwith a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy.Also provided are methods of predicting the efficacy of treatment with aRET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy ina subject having cancer that include: determining whether a cancer cellin a sample obtained from the subject has one or more RET inhibitorresistance mutations (that confer increased resistance to a cancer cellor tumor to treatment with a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, e.g., a substitution at amino acid position 804, e.g., V804M,V804L, or V804E); and determining that treatment with a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy is less likely to beeffective in a subject having a cancer cell in a sample obtained fromthe subject that has one or more RET inhibitor resistance mutations(that confer increased resistance to a cancer cell or tumor to treatmentwith a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E).Also provided are methods of predicting the efficacy of treatment with aRET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy ina subject having cancer that include: determining that treatment with aRET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy isless likely to be effective in a subject having a cancer cell in asample obtained from the subject that has one or more RET inhibitorresistance mutations (that confer increased resistance to a cancer cellor tumor to treatment with a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, e.g., a substitution at amino acid position 804, e.g., V804M,V804L, or V804E).

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a RET inhibitor that isnot a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof, to the subject for a period of time; (b) after(a), determining whether a cancer cell in a sample obtained from thesubject has at least one RET inhibitor resistance mutation (that confersincreased resistance to a cancer cell or tumor to treatment with a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a), e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);and (c) administering a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with another anticancer agent (e.g., any anticancer agentknown in the art, e.g., another RET inhibitor, e.g., the same RETinhibitor administered in step (a)) to the subject if the subject has acancer cell that has at least one RET inhibitor resistance mutation(that confers increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof of (a), e.g.,a substitution at amino acid position 804, e.g., V804M, V804L, orV804E); or (d) administering additional doses of the RET inhibitor thatis not a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof of step (a) to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation (thatconfers increased resistance to a cancer cell or tumor to treatment witha RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a), e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E).In some embodiments, where the subject is administered additional dosesof the RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of step (a), thesubject can also be administered another anticancer agent (e.g., anotherRET inhibitor, e.g., a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof).

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a RET inhibitor that isnot a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof, to the subject for a period of time; (b) after(a), determining whether a cancer cell in a sample obtained from thesubject has at least one RET inhibitor resistance mutation (that confersincreased resistance to a cancer cell or tumor to treatment with a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a), e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);and (c) administering a different RET inhibitor that is not a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof (different from the RET inhibitor administered in (a)) as amonotherapy or in conjunction with another anticancer agent (e.g., anyanticancer agent known in the art, e.g., another RET inhibitor, e.g.,the same RET inhibitor administered in (a)) to the subject if thesubject has a cancer cell that has at least one RET inhibitor resistancemutation (that confers increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof of (a), e.g.,a substitution at amino acid position 804, e.g., V804M, V804L, orV804E); or (d) administering additional doses of the RET inhibitor thatis not a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof of step (a) to the subject if the subject has acancer cell that does not have a RET inhibitor resistance mutation (thatconfers increased resistance to a cancer cell or tumor to treatment witha RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a), e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E).In some embodiments, where the subject is administered additional dosesof the RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of step (a), thesubject can also be administered another anticancer agent (e.g., anotherRET inhibitor, e.g., a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof that was previously administered to the subject, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);and (c) administering a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with another anticancer agent (e.g., any anticancer agentknown in the art, e.g., another RET inhibitor, e.g., the same RETinhibitor previously administered to the subject) to the subject if thesubject has a cancer cell that has at least one RET inhibitor resistancemutation (that confers increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof that waspreviously administered to the subject, e.g., a substitution at aminoacid position 804, e.g., V804M, V804L, or V804E); or (d) administeringadditional doses of the RET inhibitor that is not a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereofpreviously administered to the subject if the subject has cancer cellthat does not have a RET inhibitor resistance mutation (that confersincreased resistance to a cancer cell or tumor to treatment with a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof previouslyadministered to the subject, e.g., a substitution at amino acid position804, e.g., V804M, V804L, or V804E). In some embodiments, where thesubject is administered additional doses of the RET inhibitor that isnot a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof previously administered to the subject, thesubject can also be administered another anticancer agent (e.g., anotherRET inhibitor, e.g., a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof that was previously administered to the subject, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);and (b) administering a different RET inhibitor that is not a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof (different from the RET inhibitor previously administered to thesubject) as a monotherapy or in conjunction with another anticanceragent (e.g., any anticancer agent known in the art, e.g., another RETinhibitor, e.g., the same RET inhibitor previously administered to thesubject) to the subject if the subject has a cancer cell that has atleast one RET inhibitor resistance mutation (that confers increasedresistance to a cancer cell or tumor to treatment with a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof that was previously administered tothe subject, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E); or (d) administering additional doses of theRET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof previouslyadministered to the subject if the subject has cancer cell that does nothave a RET inhibitor resistance mutation (that confers increasedresistance to a cancer cell or tumor to treatment with a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof that was previously administered tothe subject, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E). In some embodiments, where the subject isadministered additional doses of the RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof previously administered to the subject, the subject canalso be administered another anticancer agent (e.g., another RETinhibitor, e.g., a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof).

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) administering one or more doses of a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof to the subject for aperiod of time; (b) after (a), determining whether a cancer cell in asample obtained from the subject has at least one RET inhibitorresistance mutation (that confers increased resistance to a cancer cellor tumor to treatment with a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof of (a), e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E); and (c) selecting a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with another anticancer agent (e.g., anyanticancer agent known in the art, e.g., another RET inhibitor, e.g.,the same RET inhibitor administered in step (a)) for the subject if thesubject has a cancer cell that has one or more RET inhibitor resistancemutations (that confer increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);or (d) selecting additional doses of the RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof of step (a) for the subject if the subject has a cancercell that does not have a RET inhibitor resistance mutation (thatconfers increased resistance to a cancer cell or tumor to treatment witha RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a), e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E).In some embodiments, when additional doses of the RET inhibitor that isnot a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof of step (a) are selected for the subject, themethod can further include selecting doses of another anticancer agent(e.g., another RET inhibitor, e.g., a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof) for the subject.

Also provided are methods of selecting a treatment for a subject havinga cancer that include (a) administering one or more doses of a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof to the subject for aperiod of time; (b) after (a), determining whether a cancer cell in asample obtained from the subject has at least one RET inhibitorresistance mutation (that confers increased resistance to a cancer cellor tumor to treatment with a RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof of (a), e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E); and (c) selecting a different RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof (different from the RET inhibitoradministered to the subject in (a)) as a monotherapy or in conjunctionwith another anticancer agent (e.g., any anticancer agent known in theart, e.g., another RET inhibitor, e.g., the same RET inhibitoradministered to the subject in (a)) for the subject if the subject has acancer cell that has one or more RET inhibitor resistance mutations(that confer increased resistance to a cancer cell or tumor to treatmentwith a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a), e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);or (d) selecting additional doses of the RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof of step (a) for the subject if the subject has a cancercell that does not have a RET inhibitor resistance mutation (thatconfers increased resistance to a cancer cell or tumor to treatment witha RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a), e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E).In some embodiments, when additional doses of the RET inhibitor that isnot a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof of step (a) are selected for the subject, themethod can further include selecting doses of another anticancer agent(e.g., another RET inhibitor, e.g., a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof) for the subject.

Also provided are methods of method of selecting a treatment for asubject having a cancer that include (a) determining whether a cancercell in a sample obtained from a subject having a cancer and previouslyadministered one or more doses of a RET inhibitor that is not a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof, has one or more RET inhibitor resistance mutations (that conferincreased resistance to a cancer cell or tumor to treatment with a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof that was previouslyadministered to the subject, e.g., a substitution at amino acid position804, e.g., V804M, V804L, or V804E); (b) selecting a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof as amonotherapy or in conjunction with another anticancer agent (e.g., anyanticancer agent known in the art, e.g., another RET inhibitor, e.g.,the same RET inhibitor previously administered to the subject) for thesubject if the subject has a cancer cell that has at least one RETinhibitor resistance mutation (that confers increased resistance to acancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof that was previously administered to the subject, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);or (c) selecting additional doses of the RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof previously administered to the subject if the subjecthas a cancer cell that does not have a RET inhibitor resistance mutation(that confers increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof that waspreviously administered to the subject, e.g., a substitution at aminoacid position 804, e.g., V804M, V804L, or V804E). In some embodiments,when additional doses of the RET inhibitor that is not a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatepreviously administered to the subject are selected for the subject, themethod can further include selecting doses of another anticancer agent(e.g., another RET inhibitor, e.g., a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof) for the subject.

Also provided are methods of method of selecting a treatment for asubject having a cancer that include (a) determining whether a cancercell in a sample obtained from a subject having a cancer and previouslyadministered one or more doses of a RET inhibitor that is not a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof, has one or more RET inhibitor resistance mutations (that conferincreased resistance to a cancer cell or tumor to treatment with a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof that was previouslyadministered to the subject, e.g., a substitution at amino acid position804, e.g., V804M, V804L, or V804E); (b) selecting a different RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof (different from theRET inhibitor previously administered to the subject) as a monotherapyor in conjunction with another anticancer agent (e.g., any anticanceragent known in the art, e.g., another RET inhibitor, e.g., the same RETinhibitor previously administered to the subject) for the subject if thesubject has a cancer cell that has at least one RET inhibitor resistancemutation (that confers increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof that waspreviously administered to the subject, e.g., a substitution at aminoacid position 804, e.g., V804M, V804L, or V804E); or (c) selectingadditional doses of the RET inhibitor that is not a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereofpreviously administered to the subject if the subject has a cancer cellthat does not have a RET inhibitor resistance mutation (that confersincreased resistance to a cancer cell or tumor to treatment with a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof that was previouslyadministered to the subject, e.g., a substitution at amino acid position804, e.g., V804M, V804L, or V804E). In some embodiments, when additionaldoses of the RET inhibitor that is not a compound of General Formula Ior a pharmaceutically acceptable salt or solvate previously administeredto the subject are selected for the subject, the method can furtherinclude selecting doses of another anticancer agent (e.g., another RETinhibitor, e.g., a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof) for the subject.

Also provided are methods of determining a subject's risk for developinga cancer that has some resistance to a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof that include: determining whether a cell in a sampleobtained from the subject has one or more RET inhibitor resistancemutations (that confer increased resistance to a cancer cell or tumor totreatment with a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);and identifying a subject having a cell that has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E), as having an increased likelihood of developinga cancer that has some resistance to a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof. Also provided are methods of determining a subject'srisk for developing a cancer that has some resistance to a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof that include: identifying a subjecthaving a cell that has one or more RET inhibitor resistance mutations(that confer increased resistance to a cancer cell or tumor to treatmentwith a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E),as having an increased likelihood of developing a cancer that has someresistance to a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof. Alsoprovided are methods of determining the presence of a cancer that hassome resistance to a RET inhibitor that is not a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof thatincludes: determining whether a cancer cell in a sample obtained fromthe subject has one or more RET inhibitor resistance mutations (thatconfer increased resistance to a cancer cell or tumor to treatment witha RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, e.g., asubstitution at amino acid position 804, e.g., V804M, V804L, or V804E);and determining that a subject having a cancer cell that has one or moreRET inhibitor resistance mutations (that confer increased resistance toa cancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, e.g., a substitution at amino acid position 804, e.g.,V804M, V804L, or V804E), has a cancer that has some resistance to a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. Also provided aremethods of determining the presence of a cancer that has some resistanceto a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof in a subject thatinclude: determining that a subject having a cancer cell that has one ormore RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a RET inhibitorthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, e.g., a substitution at amino acidposition 804, e.g., V804M, V804L, or V804E), has a cancer that has someresistance to a RET inhibitor that is not a compound of General FormulaI or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments of any of the methods described herein, a RETinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, can be any of the RET inhibitor resistance mutationslisted in Table 3 or 4 (e.g., a substitution at amino acid position 804,e.g., V804M, V804L, or V804E).

In some embodiments, the presence of one or more RET inhibitorresistance mutations in a tumor causes the tumor to be more resistant totreatment with a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof. Methods useful when a RET inhibitorresistance mutation causes the tumor to be more resistant to treatmentwith a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof are described below. For example, providedherein are methods of treating a subject having a cancer that include:identifying a subject having a cancer cell that has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof); andadministering to the identified subject a treatment that does notinclude a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof as a monotherapy. Also provided are methods oftreating a subject identified as having a cancer cell that has one ormore RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof) that include administering to the subject a treatment that doesnot include a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy. Also provided aremethods of selecting a treatment for a subject having a cancer thatinclude: identifying a subject having a cancer cell that has one or moreRET inhibitor resistance mutations (that confer increased resistance toa cancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof); and selectinga treatment that does not include a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy forthe identified subject. Also provided are methods of selecting atreatment for a subject having a cancer that include: selecting atreatment that does not include a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy fora subject identified as having a cancer cell that has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof). Also providedare methods of selecting a subject having a cancer for a treatment thatdoes not include a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy that include:identifying a subject having a cancer cell that has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof); and selectingthe identified subject for a treatment that does not include a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy. Also provided are methods of selecting asubject having a cancer for a treatment that does not include a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy that include: selecting a subject identified ashaving a cancer cell that has one or more RET inhibitor resistancemutations (that confer increased resistance to a cancer cell or tumor totreatment with a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof), for a treatment that does notinclude a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof as a monotherapy. Also provided are methods ofdetermining the likelihood that a subject having a cancer will have apositive response to treatment with a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapythat include: determining whether a cancer cell in a sample obtainedfrom the subject has one or more RET inhibitor resistance mutations(that confer increased resistance to a cancer cell or tumor to treatmentwith a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof); and determining that a subject having a cancercell that has one or more RET inhibitor resistance mutations (thatconfer increased resistance to a cancer cell or tumor to treatment witha compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof), has a decreased likelihood of having a positiveresponse to treatment with a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy.Also provided are methods of determining the likelihood that a subjecthaving cancer will have a positive response to treatment with a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy that include: determining that a subject havinga cancer cell that has one or more RET inhibitor resistance mutations(that confer increased resistance to a cancer cell or tumor to treatmentwith a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof), has a decreased likelihood of having apositive response to treatment with a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as a monotherapy.Also provided are methods of predicting the efficacy of treatment with acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof as a monotherapy in a subject having cancer thatinclude: determining whether a cancer cell in a sample obtained from thesubject has one or more RET inhibitor resistance mutations (that conferincreased resistance to a cancer cell or tumor to treatment with acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof); and determining that treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy is less likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has oneor more RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof). Also provided are methods of predicting the efficacy oftreatment with a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof as a monotherapy in a subject havingcancer that include: determining that treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof as a monotherapy is less likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has oneor more RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof).

Also provided are methods of treating a subject having a cancer thatinclude: (a) administering one or more doses of a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof for aperiod of time; (b) after (a), determining whether a cancer cell in asample obtained from the subject has one or more RET inhibitorresistance mutations (that confer increased resistance to a cancer cellor tumor to treatment with a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of (a)); and (c)administering a different RET inhibitor (e.g., a compound that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof that is differentfrom that administered in step (a)) as a monotherapy or in conjunctionwith another anticancer agent (e.g., any of the RET inhibitors describedherein, e.g., a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, e.g., the same compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereofadministered in (a)) to a subject having a cancer cell that has one ormore RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof of (a)); or (d) administering additional doses of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof of step (a) to a subject having a cancer cell that does not havea RET inhibitor resistance mutation (that confers increased resistanceto a cancer cell or tumor to treatment with a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof of(a)). In some embodiments, where the subject is administered additionaldoses of the compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof of step (a), the subject can also beadministered another anticancer agent (e.g., another RET inhibitor,e.g., a RET inhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof that is different from the compound of step (a)).

Also provided are methods of treating a subject having a cancer thatinclude: (a) determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered one or more dosesof a compound of General Formula I or a pharmaceutically acceptable saltor solvate thereof, has one or more RET inhibitor resistance mutations(that confer increased resistance to a cancer cell or tumor to treatmentwith a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof that was previously administered to thesubject); (b) administering a different RET inhibitor (e.g., a compoundthat is not a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof that isdifferent from the compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof previously administered to thesubject) as a monotherapy or in conjunction with another anticanceragent (e.g., any of the RET inhibitors described herein, e.g., acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, e.g., the same compound of General Formula I or apharmaceutically acceptable salt or solvate thereof previouslyadministered to the subject) to a subject having a cancer cell that hasone or more RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof that was previously administered to the subject); or (c)administering additional doses of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof previouslyadministered to a subject having a cancer cell that does not have a RETinhibitor resistance mutation (that confers increased resistance to acancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof that waspreviously administered to the subject). In some embodiments, where thesubject is administered additional doses of the compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof ofstep (a), the subject can also be administered another anticancer agent(e.g., another RET inhibitor, e.g., a RET inhibitor that is not acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof that is differentfrom the compound of step (a)).

Also provided are methods of selecting a treatment for a subject havinga cancer that include: (a) administering one or more doses of a compoundof General Formula I or a pharmaceutically acceptable salt or solvatethereof to the subject for a period of time; (b) after (a), determiningwhether a cancer cell in a sample obtained from the subject has one ormore RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof of (a)); and (c) selecting a different RET inhibitor (e.g., acompound that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof that is different from that administered in step (a)) as amonotherapy or in conjunction with another anticancer agent (e.g., anyof the RET inhibitors described herein, e.g., a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof,e.g., the same compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof administered in (a)) for the subjectif the subject has a cancer cell that has a RET inhibitor resistancemutation (that confer increased resistance to a cancer cell or tumor totreatment with a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof of (a)); or (d) selecting additionaldoses of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof of step (a) for the subject if thesubject has a cancer cell that does not have a RET inhibitor resistancemutation (that confers increased resistance to a cancer cell or tumor totreatment with a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof of (a)). In some embodiments, whereadditional doses of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof of step (a) areselected for the subject, the method can also include further selectinganother anticancer agent (e.g., another RET inhibitor, e.g., a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof that is different from the compound of step (a)).

Also provided are methods of selecting a treatment for a subject havinga cancer that include: (a) determining whether a cancer cell in a sampleobtained from a subject having a cancer and previously administered oneor more doses of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, has one or more RET inhibitorresistance mutations (that confer increased resistance to a cancer cellor tumor to treatment with a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof that was previouslyadministered to the subject); (b) selecting a different RET inhibitor(e.g., a compound that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof that is different from the compound of General Formula I or apharmaceutically acceptable salt or solvate thereof previouslyadministered to the subject) as a monotherapy or in conjunction withanother anticancer agent (e.g., any of the RET inhibitors describedherein, e.g., a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, e.g., the same compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereofpreviously administered to the subject) for the subject if the subjecthas a cancer cell that has a RET inhibitor resistance mutation (thatconfers increased resistance to a cancer cell or tumor to treatment witha compound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof that was previously administered to the subject); or (c)selecting additional doses of the compound of General Formula I or apharmaceutically acceptable salt or solvate thereof previouslyadministered to the subject if the subject has a cancer cell that doesnot have a RET inhibitor resistance mutation (that confers increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof that was previously administered to the subject). In someembodiments, where additional doses of a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof of step (a) areselected for the subject, the method can also include further selectinganother anticancer agent (e.g., another RET inhibitor, e.g., a RETinhibitor that is not a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof that is different from the compound of step (a)).

Also provided are methods of determining a subject's risk for developinga cancer that has some resistance to a compound of General Formula I ora pharmaceutically acceptable salt or solvate thereof that include:determining whether a cell in a sample obtained from the subject has oneor more RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof); and identifying the subject if the subject has a cell that hasone or more RET inhibitor resistance mutations (that confer increasedresistance to a cancer cell or tumor to treatment with a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof), as having an increased likelihood of developing a cancer thathas some resistance to a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. Also provided aremethods of determining a subject's risk for developing a cancer that hassome resistance to a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof that include: identifying a subjecthaving a cell that has one or more RET inhibitor resistance mutations(that confer increased resistance to a cancer cell or tumor to treatmentwith a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof), as having an increased likelihood ofdeveloping a cancer that has some resistance to a compound of GeneralFormula I or a pharmaceutically acceptable salt or solvate thereof. Alsoprovided are methods of determining the presence of a cancer that hassome resistance to a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof that includes: determining whether acancer cell in a sample obtained from the subject has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof); anddetermining that a subject having a cancer cell that has one or more RETinhibitor resistance mutations (that confer increased resistance to acancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof), has a cancerthat has some resistance to a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof. Also provided aremethods of determining the presence of a cancer that has some resistanceto a compound of General Formula I or a pharmaceutically acceptable saltor solvate thereof in a subject that include: determining that a subjecthaving a cancer cell that has one or more RET inhibitor resistancemutations (that confer increased resistance to a cancer cell or tumor totreatment with a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof), has a cancer that has someresistance to a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof.

In some embodiments of any of the methods described herein, a RETinhibitor resistance mutation that confers increased resistance to acancer cell or tumor to treatment with a compound of General Formula Ior a pharmaceutically acceptable salt or solvate thereof, can be any ofthe RET inhibitor resistance mutations listed in Table 3 or 4.

Methods of determining the level of resistance of a cancer cell or atumor to a RET inhibitor (e.g., any of the RET inhibitors describedherein or known in the art) can be determined using methods known in theart. For example, the level of resistance of a cancer cell to a RETinhibitor can be assessed by determining the IC₅₀ of a RET inhibitor(e.g., any of the RET inhibitors described herein or known in the art)on the viability of a cancer cell. In other examples, the level ofresistance of a cancer cell to a RET inhibitor can be assessed bydetermining the growth rate of the cancer cell in the presence of a RETinhibitor (e.g., any of the RET inhibitors described herein). In otherexamples, the level of resistance of a tumor to a RET inhibitor can beassessed by determining the mass or size of one or more tumors in asubject over time during treatment with a RET inhibitor (e.g., any ofthe RET inhibitors described herein). In other examples, the level ofresistance of a cancer cell or a tumor to a RET inhibitor can beindirectly assessed by determining the activity of a RET kinaseincluding one or more of the RET inhibitor resistance mutations (i.e.,the same RET kinase expressed in a cancer cell or a tumor in a subject).The level of resistance of a cancer cell or tumor having one or more RETinhibitor resistance mutations to a RET inhibitor is relative to thelevel of resistance in a cancer cell or tumor that does not have a RETinhibitor resistance mutation (e.g., a cancer cell or tumor that doesnot have the same RET inhibitor resistance mutations, a cancer cell or atumor that does not have any RET inhibitor resistance mutations, or acancer cell or a tumor that expresses a wildtype RET protein). Forexample, the determined level of resistance of a cancer cell or a tumorhaving one or more RET inhibitor resistance mutations can be greaterthan about 1%, greater than about 2%, greater than about 3%, greaterthan about 4%, greater than about 5%, greater than about 6%, greaterthan about 7%, greater than about 8%, greater than about 9%, greaterthan about 10%, greater than about 11%, greater than about 12%, greaterthan about 13%, greater than about 14%, greater than about 15%, greaterthan about 20%, greater than about 25%, greater than about 30%, greaterthan about 35%, greater than about 40%, greater than about 45%, greaterthan about 50%, greater than about 60%, greater than about 70%, greaterthan about 80%, greater than about 90%, greater than about 100%, greaterthan about 110%, greater than about 120%, greater than about 130%,greater than about 140%, greater than about 150%, greater than about160%, greater than about 170%, greater than about 180%, greater thanabout 190%, greater than about 200%, greater than about 210%, greaterthan about 220%, greater than about 230%, greater than about 240%,greater than about 250%, greater than about 260%, greater than about270%, greater than about 280%, greater than about 290%, or greater thanabout 300% of the level of resistance in a cancer cell or tumor thatdoes not have a RET inhibitor resistance mutation (e.g., a cancer cellor tumor that does not have the same RET inhibitor resistance mutations,a cancer cell or a tumor that does not have any RET inhibitor resistancemutations, or a cancer cell or a tumor that expresses a wildtype RETprotein).

RET is thought to play an important role in the development and survivalof afferent nociceptors in the skin and gut. RET kinase knock-out micelack enteric neurons and have other nervous system anomalies suggestingthat a functional RET kinase protein product is necessary duringdevelopment (Taraviras, S. et al., Development, 1999, 126:2785-2797).Moreover population studies of patients with Hirschsprung's diseasecharacterized by colonic obstruction due to lack of normal colonicenervation have a higher proportion of both familial and sporadic lossof function RET mutations (Butler Tjaden N., et al., Transl. Res., 2013,162: 1-15). Irritable bowel syndrome (IBS) is a common illness affecting10-20% of individuals in developed countries and is characterized byabnormal bowel habits, bloating and visceral hypersensitivity(Camilleri, M., N. Engl. J. Med., 2012, 367: 1626-1635). While theetiology of IBS is unknown it is thought to result from either adisorder between the brain and gastrointestinal tract, a disturbance inthe gut microbiome or increased inflammation. The resultinggastrointestinal changes affect normal bowel transit resulting in eitherdiarrhea or constipation. Furthermore in many IBS patients thesensitization of the peripheral nervous system results in visceralhypersensitivity or allodynia (Keszthelyi, D., Eur. J. Pain, 2012, 16:1444-1454). See, e.g., U.S. Publication No. 2015/0099762.

Accordingly, provided herein are methods for treating a patientdiagnosed with (or identified as having) an irritable bowel syndrome(IBS) including diarrhea-predominant, constipation-predominant oralternating stool pattern, functional bloating, functional constipation,functional diarrhea, unspecified functional bowel disorder, functionalabdominal pain syndrome, chronic idiopathic constipation, functionalesophageal disorders, functional gastroduodenal disorders, functionalanorectal pain, and inflammatory bowel disease that includeadministering to the patient a therapeutically effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof.

Also provided herein are methods for treating a patient identified ordiagnosed as having a RET-associated irritable bowel syndrome (IBS)(e.g., a patient that has been identified or diagnosed as having aRET-associated irritable bowel syndrome (IBS) through the use of aregulatory agency-approved, e.g., FDA-approved, kit for identifyingdysregulation of a RET gene, a RET kinase, or expression or activity orlevel of any of the same, in a patient or a biopsy sample from thepatient) that include administering to the patient a therapeuticallyeffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof.

Also provided herein are methods for treating pain associated with IBSthat include administering to the patient a therapeutically effectiveamount of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof is administered in combination with another therapeutic agentuseful for treating one or more symptoms of IBS.

Also provided are methods for treating an irritable bowel syndrome (IBS)in a patient in need thereof, the method comprising: (a) determining ifthe irritable bowel syndrome (IBS) in the patient is a RET-associatedIBS (e.g., using a regulatory-agency approved, e.g., FDA-approved, kitfor identifying dysregulation of a RET gene, a RET kinase, or expressionor activity or level of any of the same, in a patient or a biopsy samplefrom the patient, or by performing any of the non-limiting examples ofassays described herein); and (b) if the IBS is determined to be aRET-associated IBS, administering to the patient a therapeuticallyeffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds of the present invention are usefulfor treating irritable bowel syndrome (IBS) in combination with one ormore additional therapeutic agents or therapies effective in treatingthe irritable bowel syndrome that work by the same or a differentmechanism of action. The at least one additional therapeutic agent maybe administered with a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof as part of the sameor separate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice known to one skilled inthe art.

Non-limiting examples of additional therapeutics for the treatment ofirritable bowel syndrome (IBS) include probiotics, fiber supplements(e.g., psyllium, methylcellulose), anti-diarrheal medications (e.g.,loperamide), bile acid binders (e.g., cholestyramine, colestipol,colesevelam), anticholinergic and antispasmodic medications (e.g.,hyoscyamine, dicyclomine), antidepressant medications (e.g., tricyclicantidepressant such as imipramine or notriptyline or a selectiveserotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine),antibiotics (e.g., rifaximin), alosetron, and lubiprostone.

Accordingly, also provided herein are methods of treating irritablebowel syndrome (IBS), comprising administering to a patient in needthereof a pharmaceutical combination for treating IBS which comprises(a) a compound of General Formula I or pharmaceutically acceptable saltor solvate thereof, (b) an additional therapeutic agent, and (c)optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of IBS,wherein the amounts of the compound of General Formula I orpharmaceutically acceptable salt or solvate thereof and the additionaltherapeutic agent are together effective in treating the IBS. In oneembodiment, the compound of General Formula I or pharmaceuticallyacceptable salt or solvate thereof, and the additional therapeutic agentare administered simultaneously as separate dosages. In one embodiment,the compound of General Formula I or pharmaceutically acceptable salt orsolvate thereof, and the additional therapeutic agent are administeredas separate dosages sequentially in any order, in jointlytherapeutically effective amounts, e.g. in daily or intermittentlydosages. In one embodiment, compound of General Formula I orpharmaceutically acceptable salt or solvate thereof, and the additionaltherapeutic agent are administered simultaneously as a combined dosage.

Also provided herein is (i) a pharmaceutical combination for treatingirritable bowel syndrome in a patient in need thereof, which comprises(a) a compound of General Formula I or a pharmaceutically acceptablesalt or solvate thereof, (b) at least one additional therapeutic agent(e.g., any of the exemplary additional therapeutic agents describedherein for treating irritable bowel syndrome or known in the art), and(c) optionally at least one pharmaceutically acceptable carrier forsimultaneous, separate or sequential use for the treatment of irritablebowel syndrome, wherein the amounts of the compound of General Formula Ior pharmaceutically acceptable salt or solvate thereof and of theadditional therapeutic agent are together effective in treating theirritable bowel syndrome; (ii) a pharmaceutical composition comprisingsuch a combination; (iii) the use of such a combination for thepreparation of a medicament for the treatment of irritable bowelsyndrome; and (iv) a commercial package or product comprising such acombination as a combined preparation for simultaneous, separate orsequential use; and to a method of treatment of irritable bowel syndromein a patient in need thereof. In one embodiment the patient is a human.

The term “pharmaceutical combination”, as used herein, refers to apharmaceutical therapy resulting from the mixing or combining of morethan one active ingredient and includes both fixed and non-fixedcombinations of the active ingredients. The term “fixed combination”means that a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof and at least one additionaltherapeutic agent (e.g., an agent effective in treating irritable bowelsyndrome), are both administered to a patient simultaneously in the formof a single composition or dosage. The term “non-fixed combination”means that a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof and at least one additionaltherapeutic agent (e.g., an agent effective in treating irritable bowelsyndrome) are formulated as separate compositions or dosages, such thatthey may be administered to a patient in need thereof simultaneously,concurrently or sequentially with variable intervening time limits,wherein such administration provides effective levels of the two or morecompounds in the body of the patient. In one embodiment, the compound ofFormula I and the additional therapeutic agent are formulated asseparate unit dosage forms, wherein the separate dosages forms aresuitable for either sequential or simultaneous administration. Thesealso apply to cocktail therapies, e.g. the administration of three ormore active ingredients.

In some embodiments, a compound provided herein can be used as an agentfor supportive care for a patient undergoing cancer treatment. Forexample, a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof, can be useful to reduce one or moresymptoms associated with treatment with one or more cancer therapiessuch as diarrheal or constipations complications and/or abdominal pain.See, for example, U.S. Publication No. 2015/0099762 and Hoffman, J. M.et al. Gastroenterology (2012) 142:844-854. Accordingly, a compound, ora pharmaceutically acceptable salt thereof, or composition providedherein can be administered to a patient to address one or morecomplications associated with cancer treatment (e.g., gastrointestinalcomplications such as diarrhea, constipation, or abdominal pain).

In some embodiments, a therapeutically effective amount of a compound ofGeneral Formula I or a pharmaceutically acceptable salt or solvatethereof, can be administered to a patient undergoing cancer treatment(e.g., a patient experiencing an adverse event associated with cancertreatment such as an immune-related adverse event or a gastrointestinalcomplication including diarrhea, constipation, and abdominal pain). Forexample, a compound provided herein, or a pharmaceutically acceptablesalt thereof, can be used in the treatment of colitis or IBS associatedwith administration of a checkpoint inhibitor; see, e.g., Postow, M. A.et al. Journal of Clinical Oncology (2015) 33: 1974-1982. In some suchembodiments, a compound provided herein, or a pharmaceuticallyacceptable salt thereof, can be formulated to exhibit lowbioavailability and/or be targeted for delivery in the gastrointestinaltract. See, for example, U.S. Pat. No. 6,531,152.

Also provided is a method for inhibiting RET kinase activity in a cell,comprising contacting the cell with a compound of General Formula I. Inone embodiment, the contacting is in vitro. In one embodiment, thecontacting is in vivo. In one embodiment, the contacting is in vivo,wherein the method comprises administering an effective amount of acompound of General Formula I or a pharmaceutically acceptable salt orsolvate thereof to a subject having a cell having RET kinase activity.In some embodiments, the cell is a cancer cell. In one embodiment, thecancer cell is any cancer as described herein. In some embodiments, thecancer cell is a RET-associated cancer cell. In some embodiments, thecell is a gastrointestinal cell.

Also provided is a method for inhibiting RET kinase activity in amammalian cell, comprising contacting the cell with a compound ofGeneral Formula I. In one embodiment, the contacting is in vitro. In oneembodiment, the contacting is in vivo. In one embodiment, the contactingis in vivo, wherein the method comprises administering an effectiveamount of a compound of General Formula I or a pharmaceuticallyacceptable salt or solvate thereof to a mammal having a cell having RETkinase activity. In some embodiments, the mammalian cell is a mammaliancancer cell. In one embodiment, the mammalian cancer cell is any canceras described herein. In some embodiments, the mammalian cancer cell is aRET-associated cancer cell. In some embodiments, the mammalian cell is agastrointestinal cell.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a RET kinase with a compound provided hereinincludes the administration of a compound provided herein to anindividual or patient, such as a human, having a RET kinase, as well as,for example, introducing a compound provided herein into a samplecontaining a cellular or purified preparation containing the RET kinase.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof as defined herein

The phrase “effective amount” means an amount of compound that, whenadministered to a patient in need of such treatment, is sufficient to(i) treat a RET kinase-associated disease or disorder, (ii) attenuate,ameliorate, or eliminate one or more symptoms of the particular disease,condition, or disorder, or (iii) delay the onset of one or more symptomsof the particular disease, condition, or disorder described herein. Theamount of a compound of General Formula I that will correspond to suchan amount will vary depending upon factors such as the particularcompound, disease condition and its severity, the identity (e.g.,weight) of the patient in need of treatment, but can nevertheless beroutinely determined by one skilled in the art.

When employed as pharmaceuticals, the compounds of General Formula I canbe administered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Oral administrationcan include a dosage form formulated for once-daily or twice-daily (BID)administration. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal intramuscular or injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable

Also provided herein are pharmaceutical compositions which contain, asthe active ingredient, a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof, in combination withone or more pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions provided herein, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders. In one embodiment, the composition is formulated for oraladministration. In one embodiment, the composition is formulated as atablet or capsule.

The compositions comprising a compound of General Formula I or apharmaceutically acceptable salt or solvate thereof can be formulated ina unit dosage form, each dosage containing from about 5 to about 1,000mg (1 g), more usually about 100 mg to about 500 mg, of the activeingredient. The term “unit dosage form” refers to physically discreteunits suitable as unitary dosages for human subjects and other patients,each unit containing a predetermined quantity of active material (i.e.,a compound for General Formula I as provided herein) calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient.

In some embodiments, the compositions provided herein contain from about5 mg to about 50 mg of the active ingredient. One having ordinary skillin the art will appreciate that this embodies compounds or compositionscontaining about 5 mg to about 10 mg, about 10 mg to about 15 mg, about15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40mg to about 45 mg, or about 45 mg to about 50 mg of the activeingredient.

In some embodiments, the compositions provided herein contain from about50 mg to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 50 mg to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about450 mg to about 500 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about500 mg to about 1,000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 500 mg to about 550 mg, about 550 mg toabout 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg toabout 950 mg, or about 950 mg to about 1,000 mg of the activeingredient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

Provided herein are pharmaceutical kits useful, for example, in thetreatment of RET-associated diseases or disorders, such as cancer orirritable bowel syndrome (IBS), which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound provided herein. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

EXAMPLES

The following examples illustrate the invention.

BIOLOGICAL EXAMPLES Example A RET Enzyme Assay

Compounds of General Formula I were screened for their ability toinhibit wild type and V804M mutant RET kinase using CisBio's HTRF®KinEASE™-TK assay technology. Briefly, N-terminal GST tagged recombinanthuman RET cytoplasmic domain (aa 658-end) from Eurofins (0.25 nM RET;Cat. No. 14-570M) or N-terminal GST tagged recombinant human V804Mmutant RET cytoplasmic domain (aa 658-end) from Millipore (0.25 nMenzyme; Cat. No. 14-760) was incubated with 250 nM TK-substrate biotin(CisBio, part of Cat. No. 62TKOPEC) and 1 mM ATP along with testcompound in a buffer consisting of 25 mM HEPES pH 7.4, 10 mM MgCl₂,0.01% Triton X-100, and 2% DMSO in a volume of 8 μL. Compounds weretypically prepared in a threefold serial dilution in DMSO and added tothe assay to give the appropriate final concentration. After a 30-minuteincubation at 22° C., the reaction was quenched by adding 8 μL of quenchsolution containing 31.25 nM Sa-XL665 and 1×TK-ab-Cryptate in HTRFdetection buffer (all from CisBio, part of Cat. No. 62TKOPEC). After a 1hour incubation at 22° C., the extent of reaction was determined using aPerkinElmer EnVision multimode plate reader via HTRF dual wavelengthdetection, and the percent of control (POC) was calculated using aratiometric emission factor. 100 POC was determined using no testcompounds and 0 POC was determined using pre-quenched control reactions.The POC values were fit to a 4 parameter logistic curve, and the IC₅₀ isdefined as the concentration of inhibitor at which the POC equals 50 forthe fitted curve. The IC₅₀ values for the compounds tested in this assayare provided in Table 5.

Example B REt Cell Assay

The cellular potency of a compound inhibiting RET kinase was determinedin HEK-293 cells expressing a Kif5b-RET fusion protein. Briefly, HEK-293cells expressing a Kif5b-RET fusion protein were plated at 50Kcells/well in 96 well poly-D-Lysine coated plates the day prior to theassay. The cells were incubated for 1 hour with test compound in DMEM(Dulbecco's Modified Eagle Medium) at a final DMSO concentration of0.5%. Compounds were typically prepared in a three fold serial dilutionin DMSO and added to the assay to give the appropriate finalconcentration. After 1 hour the media was removed, the cells were fixedwith 3.8% formaldehyde for 20 min, washed with PBS, and permeabilizedfor 10 min with 100% methanol. The plates were then washed withPBS-0.05% Tween20, and blocked with LI-COR Blocking solution (LI-CORcatalog #927-40000) for 1 hour. Plates were washed with PBS-0.05%Tween20, then incubated with anti-phospho-RET(Tyr1062) (Santa Cruzcatalog #sc-20252-R) antibody and anti-GAPDH (Millipore catalog #MAB374) antibody for 2 hours. The plates were washed with PBS-0.05%Tween20, and incubated with anti-rabbit 680 (Molecular Probes cat#A21109) and anti-mouse 800 (LI-COR catalog #926-32210) secondaryantibodies for 1 hour. All antibodies were diluted in LI-COR Blockcontaining 0.05% Tween. The plates were washed with PBS-0.05% Tween20,100 μL PBS was added to each well, and the plates were read on a LI-CORAerius fluorescent plate reader. The phospho-RET signal was normalizedto the GAPDH signal. 100 POC (percent of control) was determined usingno test compounds and 0 POC was determined using 1 μM of a controlinhibitor. The POC values were fit to a 4 parameter logistic curve. TheIC₅₀ value is the point where the curve crosses 50 POC. The IC₅₀ valuesfor the compounds tested in this assay are provided in Table 5.

Example C KDR Cell Assay

The cellular potency of a compound inhibiting KDR kinase was determinedin HEK-293 cells expressing an inducible human KDR protein. Briefly,HEK-293 cells expressing KDR protein were plated at 40K cells/well in96-well collagen (compounds of Example Nos. 2, 88, 290, 291, 295, 297,298, 299, 332, 333, and 339) or poly-D-lysine (all other testedcompounds) coated plates the day prior to the assay. Cells wereincubated for 4 to 6 hours to allow them to adhere to the plate and thenprotein expression is induced by the addition of 1 μg/mL Doxycyclineovernight. The cells were incubated for 1 hour with test compound inDMEM at a final DMSO concentration of 0.25%. Compounds were typicallyprepared in a three-fold serial dilution in DMSO and added to the assayto give the appropriate final concentration. After 1 hour, wells werestimulated with VEGF (75 ng/ml final; compounds of Example Nos. #2, 88,290, 291, 295, 297, 298, 299, 332, 333, 339) or VEGF (56 ng/ml final;all other tested compounds) for 5 minutes at 37 C. The media wasaspirated and 35 μL of a 1× lysis buffer was added. Plates were shakenfor 1-2 mins to finalize cell lysis. The lysate was stored at −80° C.until ready for assay. Phospho-KDR was measured using a phospho-KDR kit(Catalog #K151BOC) purchased from Meso Scale Diagnostics (Rockville,Md.) according to the manufacturer's instructions. All values areexpressed as percent of percent of control (POC). The POC values werefitted to a 4 parameter logistic curve fit and the IC₅₀ value is pointwhere the curve crosses 50 POC. The IC₅₀ values for the compounds testedin this assay are provided in Table 5.

TABLE 5 IC₅₀ values of compounds tested in the assay of Examples A, Band/or C. RET RET KIF5B-RET pKDR Cell Enzyme FRET_ATP_ pTYR1062 HEK IC₅₀V804M Cell 10% FBS Ex# (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 1 35.8 302.247.5 N/A 2 19.6 N/A 110.8 1081.9 3 11.9 N/A 119.0 N/A 4 3.1 N/A 15.9327.6 5 4.6 32.0 4.3 242.9 6 4.9 38.3 4.2 114.9 7 3.9 20.8 2.9 115.1 83.6 N/A 4.3 98.9 9 5.3 23.3 4.2 32.7 10 4.5 N/A 2.5 47.4 11 28.9 N/A123.5 N/A 12 15.4 N/A 47.6 1190.0 13 154.5 N/A 3768.9 N/A 14 4.4 N/A 3.71781.0 15 12.5 N/A 21.2 642.9 16 5.7 20.9 2.1 435.0 17 19.9 N/A 29.283.4 18 30.6 N/A 19.8 229.4 19 12.6 N/A 54.1 546.5 20 9.8 76.8 36.81647.2 21 9.4 N/A 21.3 539.8 22 14.8 162.7 22.5 630.1 23 3.8 26.6 4.845.4 24 34.0 N/A 18.9 960.5 25 5.0 14.9 1.6 269.9 26 13.0 N/A 9.6 476.127 14.2 N/A 20.0 651.4 28 89.0 N/A 240.8 N/A 29 16.4 N/A 16.4 607.5 3022.1 N/A 123.8 920.7 31 36.7 N/A 76.1 2550.8 32 23.9 N/A 108.0 749.0 3342.9 N/A 309.5 N/A 34 34.8 N/A 61.2 3038.9 35 18.9 N/A 54.6 437.1 3624.0 N/A 25.5 211.8 37 6.8 54.9 6.6 91.2 38 15.5 N/A 16.6 396.2 39 6.3N/A 2.7 83.9 40 13.7 N/A 11.2 221.5 41 22.9 N/A 29.3 871.0 42 15.8 N/A23.4 502.2 43 22.4 N/A 31.6 653.1 44 18.3 N/A 378.9 N/A 45 27.0 N/A603.9 N/A 46 9.8 N/A 2244.2 N/A 47 12.6 N/A 2076.0 N/A 48 9.7 76.2 21.9611.9 49 7.0 N/A 5.8 236.7 50 7.9 47.1 22.1 1192.6 51 4.1 N/A 3.5 267.252 17.7 N/A 340.4 N/A 53 4.4 74.6 9.9 305.2 54 12.4 N/A 66.6 1484.9 5510.4 N/A 54.9 922.5 56 16.0 N/A 35.5 895.8 57 12.7 N/A 48.6 1036.2 588.3 N/A 16.6 438.9 59 16.3 N/A 26.6 554.3 60 14.8 N/A 16.9 376.4 61 5.5N/A 5.5 148.5 62 17.3 N/A 27.7 1298.8 63 11.5 N/A 8.2 527.2 64 31.9 N/A138.9 N/A 65 8.2 N/A 39.3 901.7 66 14.1 N/A 25.4 911.1 67 19.4 N/A 60.7521.5 68 10.2 N/A 32.2 788.5 69 4.4 N/A 2.7 117.4 70 8.4 N/A 18.5 510.171 6.4 N/A 19.6 503.3 72 6.1 57.2 12.5 99.9 73 9.8 N/A 32.7 296.5 7428.8 N/A 45.9 1346.1 75 6.3 40.1 7.0 392.1 76 8.0 N/A 13.3 1009.9 77 8.0N/A 19.2 605.2 78 4.4 N/A 5.3 80.6 79 14.5 N/A 31.3 1263.1 80 33.6 N/A542.2 N/A 81 12.6 N/A 66.1 761.9 82 4.8 13.2 3.1 91.2 83 7.6 20.5 3.7135.2 84 13.0 75.0 8.3 1264.1 85 7.6 52.6 6.5 770.7 86 10.6 N/A 5.6427.8 87 5.3 N/A 3.5 5.8 88 9.8 N/A 43.3 194.8 89 10.6 59.7 6.4 189.1 905.2 39.9 4.3 24.1 91 5.6 N/A 7.5 60.1 92 41.2 N/A 535.8 N/A 93 10.1 N/A11.2 1699.2 94 8.5 N/A 8.5 1703.6 95 15.4 N/A 26.2 1307.1 96 6.3 N/A51.9 1555.3 97 12.1 78.8 12.5 751.5 98 3.6 N/A 13.0 1596.5 99 13.9 N/A406.3 N/A 100 15.3 N/A 455.5 N/A 101 11.7 N/A 13.6 868.4 102 11.7 N/A8.3 551.3 103 23.5 N/A 23.5 847.6 104 23.1 N/A 33.2 637.4 105 13.9 N/A63.0 1142.5 106 12.0 N/A 63.4 1370.3 107 22.9 N/A 42.8 893.0 108 11.1N/A 15.6 531.0 109 8.8 36.3 2.1 359.6 110 12.0 100.5 11.7 1310.3 11133.1 N/A 58.1 1957.3 112 10.3 N/A 22.7 868.9 113 11.5 105.6 11.4 653.8114 25.9 N/A 36.0 2245.3 115 32.1 N/A 59.3 3180.2 116 11.7 N/A 12.72274.6 117 6.5 N/A 10.9 353.9 118 8.0 N/A 10.7 606.0 119 29.1 N/A 74.72268.8 120 17.9 N/A 54.8 2242.9 121 12.6 N/A 56.6 1340.9 122 11.3 N/A266.7 N/A 123 19.1 N/A 67.9 1610.8 124 18.9 N/A 36.5 1859.6 125 5.6 60.56.1 615.8 126 11.7 N/A 10.8 347.2 127 2.7 13.4 2.7 13.5 128 11.6 127.711.1 554.5 129 2.9 17.3 5.0 93.5 130 20.8 152.6 33.0 2254.3 131 8.1 N/A24.7 447.0 132 11.2 65.6 16.1 1151.0 133 4.3 10.9 1.7 147.1 134 5.5 34.211.5 319.9 135 12.8 93.6 35.4 1033.2 136 9.1 50.2 11.9 1580.0 137 8.332.1 5.2 71.3 138 5.4 N/A 5.2 16.1 139 4.5 11.3 5.4 288.9 140 25.5 N/A59.1 711.9 141 7.4 N/A 13.2 203.1 142 50.2 N/A 332.7 N/A 143 34.1 361.469.8 1795.5 144 25.2 N/A 58.9 1683.1 145 13.8 N/A 29.6 682.0 146 12.3N/A 29.0 736.5 147 19.2 N/A 25.7 1288.2 148 19.8 N/A 46.7 1062.5 14916.5 N/A 21.9 563.5 150 28.3 N/A 49.3 728.4 151 44.0 N/A 70.4 1432.3 15213.6 N/A 18.5 207.3 153 9.9 N/A 12.2 164.1 154 10.1 N/A 8.7 155.5 15519.9 N/A 23.7 979.0 156 37.4 N/A 74.5 1757.6 157 29.3 N/A 56.6 893.7 15818.0 N/A 30.2 1366.2 159 23.9 N/A 89.0 1301.4 160 13.6 N/A 11.0 191.5161 6.6 N/A 3.7 48.5 162 6.1 35.7 5.4 42.0 163 23.1 N/A 42.8 991.4 1646.9 N/A 8.8 73.6 165 24.8 N/A 28.9 2019.4 166 42.8 N/A 43.1 1988.9 16734.2 N/A 48.5 779.5 168 12.1 N/A 43.3 1091.5 169 10.8 N/A 31.1 1437.8170 54.0 N/A 200.9 N/A 171 52.6 N/A 734.6 N/A 172 68.2 N/A 264.7 N/A 17317.2 N/A 32.8 1265.6 174 14.9 N/A 70.9 1218.5 175 21.6 N/A 221.6 N/A 1767.6 N/A 15.3 928.4 177 47.0 N/A 69.9 1181.4 178 9.0 N/A 10.8 426.2 17918.0 N/A 30.8 546.6 180 13.6 N/A 135.2 N/A 181 10.5 N/A 108.7 1195.3 18211.6 N/A 27.0 563.5 183 11.9 N/A 15.8 443.7 184 4.0 N/A 2.8 75.2 18511.5 77.8 14.3 627.7 186 14.3 N/A 22.5 451.2 187 15.9 N/A 20.4 871.4 18816.8 N/A 9.7 613.7 189 7.7 N/A 9.5 254.6 190 14.0 N/A 20.4 277.3 191 8.3N/A 6.3 21.8 192 12.2 N/A 30.1 932.1 193 10.1 N/A 198.7 N/A 194 6.7 N/A11.0 242.0 195 9.4 N/A 28.1 246.5 196 10.9 102.7 45.5 629.7 197 14.0 N/A39.6 1295.9 198 14.3 N/A 25.3 659.1 199 5.1 34.8 21.7 565.4 200 8.5 50.79.2 463.2 201 10.7 N/A 7.1 1152.3 202 41.7 N/A 110.4 992.3 203 5.8 16.75.2 559.7 204 27.3 N/A 12.2 429.4 205 14.4 N/A 309.2 N/A 206 14.1 N/A23.3 1195.0 207 16.2 N/A 39.1 1958.3 208 98.2 N/A 221.6 4675.2 209 5.8N/A 164.9 N/A 210 116.1 N/A 274.8 N/A 211 107.9 N/A 322.7 N/A 212 90.3N/A 300.6 N/A 213 72.9 N/A 185.3 N/A 214 14.9 36.3 4.6 597.2 215 13.7229.9 112.7 N/A 216 12.2 N/A 20.4 573.7 217 6.4 N/A 7.4 1672.4 218 7.2N/A 10.7 4793.0 219 7.8 N/A 9.0 N/A 220 9.4 N/A 10.9 616.8 221 22.1 N/A42.8 1659.8 222 6.2 N/A 1.5 257.4 223 8.7 24.2 5.8 1552.5 224 13.5 N/A34.2 555.2 225 103.6 N/A 461.7 N/A 226 31.8 N/A 57.1 1174.2 227 201.9N/A 277.5 N/A 228 54.4 N/A 80.7 4528.8 229 333.6 N/A N/A N/A 230 242.0N/A N/A N/A 231 6.9 N/A 5.6 279.4 232 12.1 N/A 24.4 812.0 233 13.6 N/A27.3 510.5 234 25.6 N/A 31.9 1209.8 235 7.4 N/A 5.1 1510.6 236 4.0 N/A3.2 476.6 237 6.1 43.9 15.8 840.2 238 5.8 N/A 5.5 420.2 239 8.7 N/A 5.8916.4 240 15.0 N/A 18.6 897.3 241 11.6 N/A 14.7 1835.1 242 4.5 N/A 6.3223.2 243 5.6 N/A 5.4 103.2 244 20.9 N/A 69.2 659.7 245 30.2 N/A 190.7N/A 246 12.0 115.0 13.6 949.5 247 48.1 N/A 167.5 N/A 248 33.2 N/A 75.31236.9 249 26.6 N/A 33.5 997.5 250 7.0 N/A 6.1 467.7 251 7.8 29.2 5.6495.3 252 11.6 N/A 4.8 655.8 253 16.1 N/A 8.4 596.3 254 9.2 N/A 12.3446.0 255 9.1 N/A 7.3 1086.2 256 12.9 N/A 4.5 735.4 257 14.9 N/A 9.31354.7 258 12.5 N/A 10.0 504.8 259 40.1 N/A 104.2 2770.3 260 83.3 N/A261.0 5000.0 261 209.2 N/A 499.4 N/A 262 19.2 N/A 41.8 617.1 263 161.9N/A 536.5 N/A 264 58.4 N/A 134.2 N/A 265 153.4 N/A 288.6 N/A 266 47.7N/A 161.5 N/A 267 11.0 N/A 13.6 2762.2 268 6.3 30.7 4.1 496.5 269 13.2N/A 17.6 1703.7 270 68.1 N/A 295.3 N/A 271 62.7 N/A 235.9 N/A 272 7.239.0 4.7 574.7 273 20.5 N/A 33.0 2138.7 274 51.2 N/A 65.6 5000.0 2751504.1 N/A N/A N/A 276 395.1 N/A N/A N/A 277 299.5 N/A N/A N/A 278 14.7N/A 22.7 137.6 279 317.5 N/A N/A N/A 280 176.5 N/A 376.4 N/A 281 179.9N/A 193.0 N/A 282 8.2 N/A 8.1 662.3 283 18.1 144.4 21.4 N/A 284 12.5 N/A5.1 663.1 285 25.8 N/A 23.8 1710.4 286 25.2 N/A 91.7 4833.8 287 137.9N/A 259.3 N/A 288 6.1 32.2 3.7 1937.1 289 29.4 N/A 38.2 229.0 290 27.7N/A 105.1 3442.2 291 38.2 N/A 137.7 917.6 292 20.8 N/A 69.4 1081.5 29323.4 N/A 73.3 531.8 294 10.7 N/A 37.0 2102.4 295 14.1 N/A 56.6 720.2 29637.4 629.4 90.6 2353.6 297 7.6 N/A 44.8 189.5 298 20.9 N/A 101.5 1831.2299 9.6 N/A 36.8 150.7 300 235.7 N/A N/A N/A 301 20.5 N/A 129.1 158.0302 49.6 N/A 168.9 2986.4 303 96.1 N/A 228.3 N/A 304 30.0 N/A 62.11614.6 305 24.3 N/A 52.2 1487.5 306 19.6 N/A 18.3 879.9 307 16.7 N/A14.2 864.3 308 68.0 N/A 194.7 N/A 309 27.6 N/A 100.8 4777.6 310 15.7 N/A71.0 1756.4 311 3046.3 N/A N/A N/A 312 606.7 N/A N/A N/A 313 39.3 87.479.2 5000.0 314 75.9 N/A 231.5 N/A 315 53.5 N/A 154.8 N/A 316 106.9 N/A169.0 N/A 317 33.0 N/A 98.3 5000.0 318 197.1 N/A 768.2 N/A 319 104.8 N/A464.5 N/A 320 36.4 N/A 97.9 5000.0 321 46.0 N/A 123.5 N/A 322 41.4 57.780.8 4860.5 323 76.4 N/A 314.3 N/A 324 144.2 N/A 673.2 N/A 325 371.8 N/A742.0 N/A 326 75.0 N/A 70.4 579.0 327 7.4 28.0 7.1 605.7 328 62.1 239.460.4 1366.5 329 23.2 N/A 45.6 381.3 330 38.3 N/A 84.0 565.9 331 31.1 N/A147.7 2352.9 332 16.2 N/A 47.0 206.6 333 63.7 251.2 155.8 2394.0 334184.4 N/A 182.1 N/A 335 30.8 N/A 147.5 N/A 336 26.5 N/A 64.3 613.7 337445.8 N/A N/A N/A 338 118.4 N/A 403.9 N/A 339 129.2 454.8 470.4 3697.1340 91.8 N/A 411.6 N/A 341 23.5 66.1 4.1 237.2 342 28.6 337.2 30.84752.2 343 67.9 662.9 34.7 1663.9 344 15.1 111.5 10.8 385.4 345 6.1 13.94.5 305.1 346 10.1 73.8 15.5 1772.6 347 14.7 88.4 166.0 N/A 348 8.1102.5 12.2 1407.4 349 10.5 31.4 5.3 403.5 350 15.9 91.1 20.8 1855.4 35110.9 61.9 6.9 1756.0 352 13.9 184.9 13.7 2203.8 353 15.3 86.1 11.41708.0 354 22.1 194.7 16.2 1293.3 355 22.4 171.3 257.1 N/A 356 12.1 40.82.5 125.9 357 30.9 1540.1 36.8 2042.9 358 5.1 57.0 3.7 160.8 359 6.732.8 3.6 910.2 360 3.9 8.9 1.1 384.8 361 24.6 129.6 54.8 N/A 362 19.9168.7 20.7 1857.7 363 11.2 48.3 6.7 2640.1 364 21.3 128.8 13.6 4360.4365 4.0 31.7 9.9 597.3 366 7.8 42.5 9.1 422.4 367 7.7 56.2 4.9 355.4 36818.8 161.6 11.9 1847.0 369 11.7 77.7 10.7 1268.3 370 2.5 9.4 3.8 29.8371 61.7 382.9 19.7 1907.8 372 492.7 5686.8 N/A N/A 373 8.9 75.3 18.71820.4 374 11.8 93.9 12.6 N/A 375 12.3 56.7 6.9 841.0 376 24.4 150.832.1 1826.2 377 48.1 348.1 18.0 2027.1 378 24.8 108.9 32.7 466.8 37941.8 331.1 126.5 N/A 380 9.8 40.9 7.3 554.6 381 22.1 198.6 21.1 811.3382 14.4 194.2 17.3 1712.9 383 17.0 220.5 19.7 639.2 384 5.5 25.2 8.91042.1 385 27.1 159.0 47.3 1968.9 386 5.6 55.0 9.4 1408.0 387 25.1 171.253.2 N/A 388 5.7 24.6 10.0 346.5 389 5.4 29.6 11.4 856.6 390 9.0 32.513.0 951.2 391 8.3 49.8 14.7 985.7 392 8.5 31.3 3.6 764.5 393 22.9 151.965.0 N/A 394 9.0 64.5 19.7 453.2 395 6.5 20.4 13.5 489.9 396 10.6 75.034.7 1464.5 397 10.8 53.6 17.7 1498.9 398 11.1 108.4 18.6 1299.1 39910.8 34.9 7.7 N/A 400 65.5 430.0 249.9 N/A 401 21.6 138.9 36.1 692.4 40241.1 314.5 76.4 N/A 403 10.8 25.6 4.6 N/A 404 13.2 66.6 7.0 N/A 405 30.8114.2 32.5 N/A 406 42.6 223.2 39.9 N/A 407 9.0 39.4 7.7 827.6 408 29.0184.2 16.9 1298.2 409 49.2 283.7 36.0 1666.7 410 38.4 240.6 103.7 1633.0411 7.9 54.3 30.1 263.3 412 21.6 146.2 18.2 2133.2 413 15.6 105.9 29.1549.1 414 41.3 200.3 41.5 2280.9 415 25.2 157.6 25.4 2028.6 416 46.1344.8 70.8 N/A 417 37.1 283.3 48.5 N/A 418 14.7 105.3 28.1 1510.9 41929.2 127.9 31.1 1901.3 420 10.9 28.1 5.6 791.7 421 18.0 111.7 11.01620.8 422 12.9 79.3 13.1 941.5 423 7.6 29.7 5.5 1368.4 424 6.6 19.1 7.3629.8 425 25.6 71.4 10.2 916.1 426 14.3 52.8 12.6 1252.0 427 8.2 26.15.3 936.7 428 10.5 22.7 7.0 879.9 429 9.1 23.9 4.6 1563.9 430 7.5 31.85.4 791.0 431 24.5 145.2 11.6 1498.2 432 6.1 14.2 3.6 263.0 433 9.7 52.26.0 1075.2 434 6.5 65.6 10.8 1695.5 435 14.0 109.6 12.7 1327.2 436 14.9110.2 9.5 536.5 437 15.1 118.8 25.7 1971.4 438 6.1 47.3 4.8 1988.4 43911.8 46.1 5.0 1239.7 440 13.6 127.4 17.3 1694.5 441 4.7 12.5 4.2 576.5442 12.0 85.8 24.8 1672.7 443 6.6 23.0 5.3 652.8 444 12.2 76.6 15.01286.9 445 12.2 79.0 10.6 1659.3 446 10.4 120.4 20.8 1473.3 447 9.0 43.73.6 667.6 448 24.2 157.4 37.4 1721.4 449 12.2 68.1 12.0 1344.7 450 5.516.9 1.6 466.8 451 4.9 23.7 4.9 593.4 452 10.0 74.7 12.1 844.4 453 17.3122.0 17.5 1684.5 454 12.9 34.0 3.3 697.8 455 14.7 48.2 4.2 464.3 45644.6 357.7 65.4 N/A 457 13.1 105.9 19.5 876.9 458 6.9 17.0 2.4 323.5 45921.4 179.2 25.0 5000.0 460 21.0 169.4 14.6 1778.9 461 7.5 14.0 1.8 129.1462 5.7 13.9 9.6 804.1 463 9.7 47.3 17.7 677.8 464 11.6 67.8 8.0 N/A 46526.7 187.6 87.1 N/A 466 24.8 191.1 43.9 2156.1 467 33.3 157.8 28.11543.6 468 11.1 45.9 10.8 N/A 469 19.9 87.2 20.0 N/A 470 99.2 397.0 38.7N/A 471 11.5 71.2 9.6 1580.2 472 9.4 92.0 17.6 1765.0 473 6.6 28.7 4.6968.4 474 4.5 18.9 4.0 304.7 475 44.3 356.6 81.8 N/A 476 48.2 396.6 90.7N/A 477 33.5 197.0 59.9 N/A 478 45.1 292.5 93.1 N/A 479 49.3 373.9 81.9N/A 480 33.6 154.9 239.3 N/A 481 49.8 248.7 118.6 N/A 482 4.4 9.3 2.4N/A 483 8.4 50.7 4.1 77.1 484 10.2 18.2 2.0 208.7 485 6.7 41.9 13.34796.9 486 N/A N/A N/A N/A 487 N/A N/A N/A N/A 488 N/A N/A N/A N/A 4894.5 5.7 3.8 19.5 490 13.9 44.7 9.6 619.4 491 31.9 63.4 3.4 119.6 492 9.045.9 16.6 563.2 493 6.9 38.3 10.4 927.5 494 28.1 202.0 96.9 1834.3 49513.6 73.0 17.3 771.3 496 22.8 161.7 69.7 2119.5 497 14.6 46.1 22.5 N/A498 17.4 70.2 34.1 N/A 499 20.1 35.3 9.0 462.0 500 9.3 29.6 12.4 457.9501 7.7 29.7 7.2 554.3 502 8.2 35.9 8.3 436.9 503 18.5 203.3 55.5 N/A504 47.9 409.2 42.4 2068.1 505 26.5 304.6 62.8 1304.3 506 31.3 69.4 6.5212.5 507 6.2 10.8 1.3 24.9 508 6.6 26.2 2.1 2.9 509 13.8 55.0 2.9 9.2510 6.7 31.1 9.6 322.9 511 27.3 62.3 11.3 1054.6 512 154.0 1006.9 213.3N/A 513 17.1 85.7 61.4 2940.0 514 528.8 3433.0 N/A N/A 515 15.3 53.510.3 284.0 516 15.3 39.4 4.4 172.6 517 19.1 39.6 23.1 1785.7 518 36.7154.1 46.4 4630.9 519 13.1 77.6 10.5 1247.6 520 69.5 572.6 164.9 N/A 5218.8 21.0 5.8 674.6 522 50.4 489.7 103.3 N/A 523 326.5 3336.8 N/A N/A 524109.5 693.3 230.6 N/A 525 20.4 173.9 59.7 1580.1 526 11.5 21.2 5.65000.0 527 14.9 110.5 29.2 917.9 528 20.2 138.9 57.0 1666.7 529 28.5148.0 79.2 5000.0 530 18.0 109.4 40.0 1535.8 531 17.0 89.8 34.3 689.7532 148.9 1578.6 811.5 N/A 533 10.9 43.7 22.2 4855.8 534 33.9 173.0 15.812.5 535 34.9 125.9 6.2 374.4 536 69.8 91.0 32.8 787.0 536 9.9 86.2 17.7655.5 538 43.4 438.2 224.3 N/A 539 13.9 177.7 73.1 1638.5 540 5.1 52.398.2 1217.5 541 5.2 135.2 95.3 534.4 542 20.7 238.6 34.8 221.7 543 15.2113.1 101.0 N/A 544 9.9 57.0 4.7 234.0 545 18.9 255.6 302.0 N/A 546 16.6128.2 35.8 810.8 547 20.4 137.9 213.3 N/A 548 72.1 545.2 99.9 N/A 54915.6 81.8 89.1 986.4 550 47.2 464.7 348.4 N/A 551 56.6 450.1 107.1 N/A552 172.0 1242.2 330.4 N/A 553 173.7 1167.2 197.6 N/A 554 267.5 1695.3N/A N/A 555 19.6 122.8 26.6 1027.6 556 50.4 397.3 38.9 1897.3 557 49.2430.6 38.3 802.0 558 12.0 122.2 9.1 548.2 559 N/A N/A N/A N/A 560 82.7504.6 94.6 N/A 561 23.8 144.9 37.5 1725.1 562 56.0 358.8 58.6 N/A 5634.4 11.7 3.8 195.3 564 6.4 30.3 26.2 740.0 565 6.4 28.7 10.3 540.3 5669.0 35.9 145.7 N/A 567 3.1 14.4 4.9 198.3 568 6.1 30.4 5000.0 N/A 5696.2 20.6 2.8 2.2 570 4.2 7.3 2.2 N/A 571 92.0 720.5 5000.0 N/A 572 58.2779.0 293.2 N/A 573 497.8 3063.1 N/A N/A 574 258.0 2925.4 N/A N/A 575N/A N/A N/A N/A 576 63.2 477.9 89.6 N/A 577 N/A N/A N/A N/A 578 N/A N/AN/A N/A 579 N/A N/A N/A N/A 580 11.5 61.3 23.5 1243.5 581 13.8 96.5 21.5670.7 582 11.6 52.5 19.3 561.0 583 865.3 6194.3 N/A N/A 584 136.5 601.4N/A N/A 585 13.6 58.4 13.2 N/A 586 5.2 40.0 15.6 5000.0 587 22.2 109.028.0 N/A 588 14.4 124.7 144.8 5000.0 589 N/A N/A N/A N/A 590 14.6 146.651.5 1486.1 591 5.7 19.5 4.1 1486.1 592 16.1 58.9 17.4 283.3 593 13.329.1 12.4 153.7 594 78.9 233.5 9.1 761.8 595 12.7 25.8 5.3 217.4 59618.5 41.9 8.7 304.9 597 34.0 172.7 39.7 830.2 598 73.6 581.0 137.7 N/A599 27.6 189.2 16.5 4859.0 600 53.0 526.5 96.3 N/A 601 N/A N/A N/A N/A602 N/A N/A N/A N/A 603 N/A N/A N/A N/A 604 N/A N/A N/A N/A 605 N/A N/AN/A N/A 606 N/A N/A N/A N/A 607 N/A N/A N/A N/A 608 N/A N/A N/A N/A 60916.5 93.8 31.5 1982.5 610 48.1 319.3 109.4 4442.3 611 11.9 26.8 2.5298.5 612 38.2 91.8 5.2 430.6 613 121.8 642.0 360.9 N/A 614 22.2 121.317.0 2303.6 615 60.0 303.3 117.3 N/A 616 60.8 269.4 85.2 N/A 617 N/A N/AN/A N/A 618 N/A N/A N/A N/A 619 62.7 414.9 128.8 5000.0 620 116.4 723.7N/A N/A 621 883.3 10000.0 N/A N/A 622 83.0 657.6 98.8 N/A 623 63.7 486.5101.9 N/A 624 397.4 1865.8 N/A N/A 625 304.7 2918.5 N/A N/A 626 35.7291.9 141.2 N/A 627 66.6 513.3 69.4 N/A 628 11.4 67.5 16.7 5000.0 62915.3 76.9 34.4 5000.0 630 10.2 26.4 11.7 N/A 631 98.1 412.1 130.2 N/A632 147.7 417.6 N/A N/A 633 136.6 1154.3 N/A N/A 634 98.9 498.9 140.2N/A 635 48.8 295.7 90.2 N/A 636 9.4 28.0 4.5 N/A 637 6.2 15.2 3.9 N/A638 16.9 76.5 15.8 N/A 639 9.2 48.8 24.6 4684.4 640 N/A N/A N/A N/A 641N/A N/A N/A N/A 642 20.5 156.5 41.0 N/A 643 377.4 841.2 N/A N/A 644 N/AN/A N/A N/A 645 26.7 81.9 40.3 1683.7 646 15.6 43.1 45.7 1958.1 647 34.4101.3 63.0 N/A 648 34.1 98.4 182.9 N/A 649 656.2 1329.7 N/A N/A 650345.4 1708.5 N/A N/A 651 208.1 382.2 N/A N/A 652 23.1 57.8 17.8 1695.6653 86.9 169.4 69.4 N/A 654 70.6 81.8 163.7 N/A 655 N/A N/A N/A N/A 656N/A N/A N/A N/A 657 139.7 174.8 215.5 N/A 658 15.0 32.3 25.1 1844.2 65974.3 92.0 173.0 N/A 660 83.2 79.7 283.4 N/A 661 112.2 413.9 N/A N/A 66210.4 58.3 13.9 N/A 663 7.5 51.3 14.7 N/A 664 4.9 11.8 6.6 N/A 665 5.920.7 2.2 N/A 666 10.4 19.1 5.9 190.7 667 8.2 32.6 12.4 N/A 668 9.5 31.010.8 N/A 669 20.6 67.8 21.1 N/A 670 32.4 183.3 36.4 N/A 671 13.3 44.513.3 N/A 672 19.3 156.9 17.3 N/A 673 12.0 30.9 11.4 N/A 674 42.5 178.174.7 N/A 675 13.6 59.3 24.1 N/A 676 9.0 41.9 15.6 N/A 677 15.4 72.2 36.0N/A 678 15.0 81.6 16.3 N/A 679 15.8 38.8 15.2 N/A 680 13.3 52.1 10.8 N/A681 33.3 281.4 81.0 N/A 682 12.6 53.1 17.5 N/A 683 36.9 147.8 67.2 N/A684 36.6 307.4 77.3 N/A 685 31.4 125.7 31.4 N/A 686 8.1 26.1 10.1 N/A687 6.5 13.3 3.7 N/A 688 7.6 15.1 3.7 50.9 689 6.3 11.9 3.8 N/A 690 12.325.7 6.0 N/A 691 11.2 51.2 19.7 N/A 692 8.2 10.2 4.7 N/A 693 8.6 15.44.4 1015.3 694 13.1 36.7 16.3 N/A 695 14.1 148.5 27.1 N/A 696 9.6 47.316.1 N/A 697 28.1 60.0 13.8 N/A 698 6.7 30.3 12.4 N/A 699 19.4 115.624.3 N/A 700 16.8 40.1 5.3 346.7 701 16.5 37.0 8.0 N/A 702 15.3 41.0 5.6N/A 703 16.4 48.1 9.8 N/A 704 30.1 99.3 8.3 N/A 705 16.7 41.3 5.1 N/A706 18.3 44.9 6.4 N/A 707 20.1 49.0 6.5 N/A 708 19.4 32.0 7.0 N/A 70926.2 70.5 9.3 N/A 710 20.0 51.6 12.6 N/A 711 15.5 31.7 26.9 N/A 712136.8 365.1 N/A N/A 713 10.8 20.1 17.0 N/A 714 18.1 29.1 7.8 N/A 71534.2 68.9 13.5 N/A 716 23.7 36.4 8.0 N/A 717 92.1 1003.8 185.5 N/A 71845.4 331.9 59.5 N/A 719 87.6 356.8 121.4 N/A 720 38.4 278.6 34.2 N/A 72136.9 174.2 76.4 N/A 722 89.4 530.4 108.6 N/A 723 17.7 62.6 18.8 N/A 72411.8 59.7 32.8 N/A 725 116.6 520.3 N/A N/A 726 389.3 3899.9 N/A N/A 72761.7 450.2 128.2 N/A 728 176.9 1497.8 N/A N/A 729 28.4 185.3 35.1 N/A730 25.8 113.4 30.5 N/A 731 19.1 98.9 37.4 N/A 732 40.7 235.0 81.5 N/A733 23.4 181.9 21.6 N/A 734 61.4 430.6 117.0 N/A 735 26.3 152.4 91.2 N/A736 35.1 189.1 67.4 N/A 737 24.7 203.3 24.4 N/A 738 31.6 109.5 69.3 N/A739 36.1 245.2 92.5 N/A 740 4.0 38.6 8.7 N/A 741 42.4 77.4 45.5 N/A 74237.3 90.0 38.5 N/A 743 184.7 282.9 N/A N/A 744 46.2 103.6 66.3 N/A N/A =Not available

SYNTHETIC EXAMPLES Synthesis of Synthetic Intermediates Examples P1 andP2 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (P1) and4-bromo-6-methoxypyrazolo[1,5-a]pyridine (P2)

Step 1: Preparation of 1-amino-3-bromo-5-methoxypyridin-1-ium2,4,6-trimethvlbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (Intermediate R1, 26.6g, 117 mmol) in DCM (570 mL) cooled to 0° C. was added3-bromo-5-methoxypyridine (22.1 g, 117 mmol) in portions. The reactionmixture was stirred for 1 h at 0° C. then treated with additional3-bromo-5-methoxypyridine (250 mg, 1.39 mmol) and stirred for anadditional 2 h at 0° C. The reaction mixture was diluted with Et₂O (600mL), stirred at 0° C. for 10 min and then vacuum filtered, rinsed withEt₂O (3×250 mL). Upon reduction in volume by about ⅓, the filtrateyielded additional precipitate which was collected by filtration. Bothfilter cakes were dried in vacuo to provide the title compound (39.3 g,83% yield). ¹H NMR (CDCl₃) δ 9.25 (br s, 1H), 8.99 (m, 1H), 8.74 (m,1H), 7.46 (m, 1H), 6.83 (s, 2H), 3.92 (s, 3H), 2.65 (s, 6H), 2.22 (s,3H).

Step 2: Preparation of Ethyl6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and Ethyl4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate

To a magnetically stirred white suspension of1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate(33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was addedTEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethylpropiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, thereaction was slowly quenched via portion-wise addition to rapidlystirring ice water (820 mL). The mixture was stirred at ambienttemperature for 10 min and then vacuum filtered. Solids collected wererinsed with water and air-dried, yielding the title compounds as anorange solid in an isomeric ratio of about 4:1 (by ¹H NMR) with the 6-Brisomer as the major isomer (21 g). The wet solid isomeric mixture (about75% w/w) was directly used in Step 3 without further purification. MS(apci) m/z=298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeOchemical shift in ¹H NMR (CDCl₃) δ 3.98 (6-Br isomer) vs. 3.83 (4-Brisomer).

Step 3: Preparation of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (P1) and4-bromo-6-methoxypyrazolo[1,5-a]pyridine (P2)

The isomeric mixture of ethyl6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate and ethyl4-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate from Step 2 (15g, 50.1 mmol) was added to 48% HBr (114 mL) while stirring, then heatedat 80° C. for 90 min followed by stirring at ambient temperatureovernight. The resulting suspension was vacuum filtered and rinsed withwater. The aqueous filtrate and the filter cake were treatedindependently. The filter cake was taken up in MTBE and vacuum filteredto remove insoluble impurities. The MTBE filtrate was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to yield6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate P1) as a beigesolid (about 98:2 6-/4-Br; 5.08 g). MS (apci) m/z=226.9, 228.9 (M+H). ¹HNMR (CDCl₃) δ 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H),3.94 (s, 3H).

Independently the original aqueous reaction mixture filtrate wasextracted with EtOAc (2×500 mL). The combined organic extracts weredried (Na₂SO₄), filtered and concentrated in vacuo. The crude residuewas taken up in DCM (50 mL) and then filtered to remove insolublesolids. Concentration of the DCM filtrate under vacuum followed bysilica chromatography (0 to 50% EtOAc/hexanes) yielded a second batch of6-bromo-4-methoxypyrazolo[1,5-a]pyridine (Intermediate P1) as whitesolid (upper R_(f) spot, 2.06 g), as well as the minor isomer titlecompound 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P2) alsoas white solid (lower R_(f) spot, 1.32 g). MS (apci) m/z=226.9, 228.9(M+H). ¹H NMR (CDCl₃) δ 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55(m, 1H), 3.80 (s, 3H).

Intermediate P3

6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde

To a 0° C. solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine(Intermediate P1, 0.75 g, 3.303 mmol) in DMF (33 mL) was slowly addedPOCl₃ (0.92 mL, 9.909 mmol). The reaction was warmed to ambienttemperature and stirred for 4 h and then diluted with H₂O (30 mL). Theresulting suspension was basified to pH 9-10 with 1 M NaOH_((aq)), thenstirred for 1 h and vacuum filtered, then rinsed sequentially with H₂O(25 mL) and MTBE (50 mL) to yield the title compound (0.76 g, 90%yield). MS (apci) m/z=256.9 (M+H).

Intermediate P4

6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile Step 1:Preparation of(E)-6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime

To a suspension of6-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (IntermediateP3, 0.76 g, 3.0 mmol) and hydroxylamine hydrochloride (0.31 g, 4.5 mmol)in EtOH (40 mL) was added water (20 mL), and the reaction was stirred at50° C. for 4 h. After cooling to ambient temperature the reactionmixture was concentrated in vacuo. The residue was suspended in water,then treated with saturated NaHCO_(3(aq)) and vacuum filtered. Thesolids were rinsed sequentially with H₂O (25 mL) and MTBE (50 mL) toyield the title compound (0.68 g, 84% yield). MS (apci) m/z=271.9 (M+H).

Step 2: Preparation of6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of(E)-6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (17.15g, 63.50 mmol) in acetic anhydride (707 mL, 7.49 mol) was heated at 120°C. overnight. Following subsequent distillation to remove the aceticanhydride, the remaining residue was dried in vacuo to yield the titlecompound (15.92 g, 99.4% yield). ¹H NMR (CDCl₃) δ 8.32 (m, 1H), 8.12 (s,1H), 6.74 (m, 1H), 4.03 (s, 3H).

Intermediate P5

3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate Step 1: Preparation of4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P4, 50 g, 198.4 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(49.53 g, 238.0 mmol) in dioxane (660 mL) was added 2 M Na₂CO_(3(aq))(297.5 mL, 595.1 mmol). The reaction mixture was sparged with nitrogenfor 20 min before Pd(PPh₃)₄ (4.584 g, 3.967 mmol) was introduced,followed by additional 5 min of sparging with nitrogen. The reaction washeated at 80° C. for 18 h, then cooled to ambient temperature andvigorously stirred for 2 h. The suspension was vacuum filtered, rinsedsequentially with H₂O (2×300 mL) and MTBE (3×300 mL), then dried invacuo overnight to yield the title compound, which was used in the nextstep without further purification (52.62 g). MS (apci), m/z=254.1 (M+H).

Step 2: Preparation of4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a suspension of4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(52.62 g, 207.8 mmol) in DCE (2 L) was added AlCl₃ (92.86 g, 696.42mmol), and the reaction mixture was stirred at 80° C. for 3 h.Additional AlCl₃ (2.5 g, 18.75 mmol) was introduced and the reaction wasrefluxed overnight. After cooling to ambient temperature the reactionmixture was diluted with DCE (1 L) and then quenched with portions ofH₂O (5×500 mL). The mixture was stirred at ambient temperature for 3 hbefore the resulting suspension was vacuum filtered and the filter cakedried in a vacuum oven (40° C.) to afford the title compound, which wasused in the next step without further purification (43.69 g). MS (apci)m/z=239.9 (M+H). ¹H NMR (d⁶-DMSO) δ 11.38 (s, 1H), 8.74 (d, 1H), 8.50(s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 6.96 (d, 1H), 3.88 (s, 3H).

Step 3: Preparation of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

To a suspension of4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(43.69 g, 182.6 mmol) in DMA (365 mL) was added DIEA (63.6 mL, 365.3mmol) followed by1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(71.77 g, 200.9 mmol). The resulting solution was stirred at ambienttemperature for 2 h and then slowly poured into H₂O (4 L). The resultingsuspension was stirred for 2 h then vacuum filtered. The filter cake wasrinsed with H₂O (3×500 mL) and air dried overnight. The filter cake wasthen dissolved in DCM (1.6 L) and the resulting biphasic mixture wasphase-separated. The organic layer was dried over anhydrous MgSO₄,filtered through Celite® and rinsed with DCM. The combined organiclayers were concentrated to yield the title compound as a 90% pure tansolid (64.3 g, 95% yield). The purity of the title compound can befurther improved to >95% via silica chromatography (0-90%acetone/hexanes). ⁹F NMR (CDCl₃) δ −72.0. ¹H NMR (CDCl₃) δ 8.66 (d, 1H),8.29 (s, 1H), 7.77 (d, 1H), 7.70 (s, 1H), 7.55 (d, 1H), 4.01 (s, 3H).

Intermediate P6

4-(6-Fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube a solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5, 500 mg, 1.35 mmol) indioxane (13 mL) was treated sequentially with2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (451mg, 2.02 mmol), Pd(PPh₃)₄ (77.8 mg, 0.0673 mmol), then 2 M Na₂CO_(3(aq))(3367 μL, 6.73 mmol). The resulting reaction mixture was sparged withnitrogen, sealed, and heated at 90° C. overnight. After cooling toambient temperature the reaction mixture was diluted with water (10 mL)and vigorously stirred. The suspension was vacuum filtered and thefilter cake was rinsed with water (3×5 mL), and subsequently dried invacuo overnight to yield the title compound (285 mg, 67% yield). MS(apci), m/z=319.0 (M+H).

Intermediate P7

6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate Step 1: Preparation of4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (IntermediateP1; 2.00 g, 227.1 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.02 g, 208.1 mmol) in dioxane (10 mL) was added 2 M Na₂CO_(3(aq)) (8.1mL, 17.6 mmol) and Pd(PPh₃)₄ (4.584 g, 3.967 mmol). The reaction mixturewas purged with nitrogen for 2 min, sealed and heated at 90° C. for 4 h.After cooling to ambient temperature, the reaction mixture was dilutedwith water (50 mL) and stirred for 30 min. The resulting suspension wasvacuum filtered, rinsed sequentially with water (2×20 mL) and Et₂O (2×10mL) to yield the crude title compound, which was used in the next stepwithout further purification. MS (apci), m/z=229.1 (M+H).

Step 2: Preparation of6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol

4-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (2.1 g,9.2 mmol) was suspended in DCE (50 mL) and treated with AlCl₃ (6.134 g,46.00 mmol). The resulting reaction mixture was heated at 90° C.overnight. Upon cooling to ambient temperature, the reaction mixture wasquenched with Na₂SO₄*10H₂O in THF (50 mL) and stirred for 2 h beforefiltering and concentrating in vacuo. The crude residue was taken up insaturated NH₄Cl_((aq)) (50 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were filtered through PS paper andconcentrated in vacuo to afford the crude title compound, which was usedin the next step without further purification. MS (apci) m/z=215.1(M+H).

Step 3: Preparation of6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

A suspension of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol(1.0 g, 4.67 mmol), DIEA (4.1 mL, 23.3 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.2 g, 6.07 mmol) in THF (20 mL) was stirred at ambient temperatureovernight, then concentrated in vacuo and purified by silicachromatography (0-20% MeOH/EtOAc) to afford the title compound (757 mg,47% yield). MS (apci) m/z=346.9 (M+H).

Intermediate P8

3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate Step 1: Preparation of6-bromo-3-chloro-4-methoxypyrazolo[1,5-a]pyridine

To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (IntermediateP1 as a partial HBr salt; 1000 mg, 4.40 mmol) in DCM (16 mL) was addedNCS (433.59 mg, 3.247 mmol) at ambient temperature. After stirringovernight, additional NCS (125 mg, 0.936 mmol) was introduced and thereaction was stirred for another 2 h. The mixture was then diluted withwater (25 mL) and extracted with DCM (2×25 mL). The combined organicextracts were washed with water, dried over anhydrous MgSO₄, filteredand concentrated to yield an 85:15 mixture of two components (1106 mg),with the major component being the title compound. ¹H NMR (CDCl₃): Majorcomponent δ 8.18 (d, 1H), 7.75 (s, 1H), 6.45 (d, 1H), 3.96 (s, 3H).Minor component δ 8.22 (d, 1H), 7.78 (s, 1H), 6.48 (d, 1H), 2.78 (s,3H). Major component: MS (apci) m/z=260.1, 262.9 (M+H). This crudemixture was used in the next without further purification.

Step 2: Preparation of3-chloro-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

In a pressure tube a suspension of6-bromo-3-chloro-4-methoxypyrazolo[1,5-a]pyridine (550 mg, 2.10 mmol) indioxane (7 mL) was treated with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(656 mg, 3.15 mmol), 2 M Na₂CO_(3(aq)) (3155 μL, 6.31 mmol) andPd(PPh₃)₄ (122 mg, 0.105 mmol). The resulting mixture was sparged withnitrogen and then heated at 90° C. overnight. After cooling to ambienttemperature the reaction mixture was diluted with water (50 mL) andextracted with DCM (2×50 mL). The combined organic extracts were driedover anhydrous MgSO₄ and filtered, and the filtrate was concentrated.The crude residue was purified by silica chromatography (25-100%EtOAc/hexanes) to provide the title compound (393 mg, 71% yield). MS(apci) m/z=263.0 (M+H). ¹H NMR (CDCl₃) δ 8.16 (d, 1H), 7.76 (s, 1H),7.75 (s, 1H), 7.62 (s, 1H), 6.46 (s, 1H), 4.01 (s, 3H), 3.99 (s, 1H).

Step 3: Preparation of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol

A suspension of3-chloro-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(1.0 g, 3.807 mmol) in 1 M BBr₃ in DCM (19.03 mL, 19.03 mmol) wasstirred overnight at ambient temperature followed by another 22 h at 40°C. Upon cooling to ambient temperature, the reaction mixture wasquenched with water (100 mL) and MeOH (10 mL). The resulting mixture wasextracted with DCM (100 mL) and 10% MeOH in DCM (2×100 mL). The combinedorganic extracts were concentrated in vacuo to provide the crude titlecompound, which was used directly in the next step without furtherpurification (1959 mg). MS (apci) m/z=249.0 (M+H).

Step 4: Preparation of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

To a suspension of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (0.95g, 3.82 mmol) in DCM (20 mL) was added DIEA (1.33 mL, 7.64 mmol)followed by1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.50 g, 4.20 mmol). The resulting suspension was stirred at ambienttemperature overnight and subsequently diluted with DCM (20 mL) andquenched with water (50 mL). The aqueous phase was extracted with DCM(3×50 mL) and the combined organic extracts were dried (MgSO₄),filtered, and concentrated. The crude residue was purified by silicachromatography (25-100% EtOAc/hexanes) to yield the title compound (860mg, 59% yield). ¹H NMR (CDCl₃) δ 8.49 (d, 1H), 7.92 (s, 1H), 7.73 (s,1H), 7.63 (s, 1H), 7.23 (d, 1H), 3.99 (s, 3H). ¹⁹F NMR (CDCl₃) δ −72.5.¹⁹F NMR (CDCl₃) δ −72.5.

Intermediate P9

3-chloro-4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

In a pressure tube a solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P8; 150 mg, 0.394 mmol) indioxane (3 mL) was treated sequentially with2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (132mg, 0.591 mmol), 2 M Na₂CO_(3(aq)) (985 μL, 1.97 mmol) and Pd(PPh₃)₄(22.8 mg, 0.0197 mmol). The reaction mixture was sparged with nitrogenand then heated at 90° C. overnight. After cooling to ambienttemperature the reaction mixture was diluted with water (10 mL) andvigorously stirred. The suspension was vacuum filtered and the filtercake was rinsed sequentially with water (10 mL) and MTBE (3×5 mL), andsubsequently dried in vacuo to yield the title compound (79 mg, 61%yield). MS (apci), m/z=327.9 (M+H).

Intermediate P10

4-Bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde

A solution of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (Intermediate P2;5.0 g, 22 mmol) in DMF (220 mL) was cooled to 0° C. and then slowlytreated with POCl₃ (6.2 mL, 66 mmol). The reaction was warmed to ambienttemperature and stirred overnight. The reaction mixture was cooled to 0°C., quenched with water (220 mL), and basified with 6 M NaOH_((aq)) topH 9-10. The reaction mixture was stirred for 1 h and then vacuumfiltered. The solids were rinsed sequentially with water (3×50 mL) andMTBE (3×50 mL). The collected solid was suspended in DCM (500 mL) andstirred in a sonicating bath for 30 min and then vacuum filtered. Thefiltrate was retained, while the filter cake was taken up in water (300mL) and extracted with DCM (2×300 mL). The organic extracts, along withthe retained DCM filtrate, were combined and dried over anhydrousNa₂SO₄, then filtered and concentrated in vacuo to provide the titlecompound (4.84 g, 86% yield). MS (apci), m/z=256.9 (M+H).

Intermediate P11

4-Bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile Step 1:Preparation of 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehydeoxime

To a suspension of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (IntermediateP10; 4.84 g, 19.0 mmol) in EtOH (253 mL) at ambient temperature wasadded water (127 mL) and hydroxylamine hydrochloride (1.98 g, 28.5mmol). After stirring at 50° C. overnight, the reaction mixture wascooled to ambient temperature and concentrated in vacuo. The residue wassuspended in water (150 mL) and then quenched slowly with saturatedNaHCO_(3(aq)) (30 mL). After stirring for 1 hour at ambient temperaturethe suspension was vacuum filtered and the filter cake rinsedsequentially with H₂O (500 mL) and MTBE (100 mL) to yield the titlecompound as a 2:1 E/Z mixture (5.13 g, quantitative yield), which wasused in the next step without further purification. MS (apci) m/z=271.9(M+H).

Step 2: Preparation of4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

The E/Z mixture from Step 1 (4.95 g, 18.33 mmol) in acetic anhydride(172.9 mL, 1833 mmol) was stirred at 140° C. for 25 h, then cooled toambient temperature. The resulting suspension was further cooled in anice bath for 15 min and then vacuum filtered and rinsed sequentiallywith water (200 mL) and MTBE (300 mL) to provide the title compound(3.74 g, 81% yield). ¹H NMR (d⁶-DMSO) δ 8.70 (s, 1H), 8.60 (s, 1H), 7.78(s, 1H), 3.83 (s, 3H).

Intermediate P12

4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

To a suspension of4-Bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP11; 1500 mg, 5.951 mmol) in DCE (10 mL) was added AlCl₃ (2380 mg, 17.85mmol), and the reaction mixture was stirred at 80° C. for 4 h. Uponcooling to ambient temperature, the reaction mixture was quenched withNa₂SO₄*10H₂O in THF (100 mL), then stirred overnight and then filteredand concentrated in vacuo to afford the title compound (963 mg, 68%yield). MS (apci) m/z=238.0 (M−H).

Intermediate P13

tert-butyl4-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube a solution of4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP12; 419 mg, 1.76 mmol) in dioxane (30 mL) was treated with tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(824 mg, 2.12 mmol), 2 M Na₂CO_(3(aq)) (1764 μL, 3.53 mmol) andPd(PPh₃)₄ (20.4 mg, 0.0176 mmol). The resulting reaction mixture wassparged with nitrogen for 5 min and then stirred at 100° C. for 4 h.After cooling to ambient temperature, the reaction mixture was dilutedwith saturated NH₄Cl(aq) (20 mL) and brine (2 mL), and then extractedwith EtOAc (3×50 mL). The combined organic extracts were filteredthrough PS paper and then concentrated in vacuo to afford the crudetitle compound, which was used without further purification. MS (apci)m/z=421.1 (M+H).

Intermediate P14

tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

Tert-butyl4-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P13; 750 mg, 1.78 mmol), DIEA (1553 μL, 8.92 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(828 mg, 2.32 mmol) were combined in THF (20 mL) and stirred at ambienttemperature overnight. The reaction was subsequently concentrated invacuo and directly purified by silica chromatography (20-100%EtOAc/hexanes) to yield the title compound (723 mg, 73% yield). MS(apci) m/z=553.1 (M+H).

Intermediate P15

4-(4-(4-(3,3-Dimethylbutanoyl)piperazin-1-yl)phenyl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube a solution of4-bromo-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile, (IntermediateP12; 500 mg, 2.10 mmol) in dioxane (10 mL) was treated with3,3-dimethyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)butan-1-one(Intermediate R11; 974 mg, 2.52 mmol), 2 M Na₂CO_(3(aq)) (2100 μL, 4.20mmol) and Pd(PPh₃)₄ (24.3 mg, 0.0210 mmol). The resulting reactionmixture was sparged with nitrogen for 5 min then heated at 100° C.overnight. After cooling to ambient temperature, the reaction mixturewas diluted with water and brine (2 mL each) and then extracted withEtOAc (2×50 mL). The combined organic extracts were filtered through PSpaper then concentrated in vacuo to afford the crude title compound,which was used without further purifications (510 mg, 58% yield). MS(apci), m/z=419.1 (M+H).

Intermediate P16

3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate

To a suspension of4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P15; 510 mg, 1.22 mmol) in THF (20 mL) was added DIEA (439μL, 2.44 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(480 mg, 1.34 mmol). This reaction mixture was stirred at ambienttemperature overnight then directly purified by silica chromatography(0-100% EtOAc/hexanes) to yield the title compound (611 mg, 91% yield).

Intermediate R1

O-(mesitylsulfonyl)hydroxylamine Step 1: Preparation of tert-butyl(mesitylsulfonyl)oxycarbamate

To a 0° C. solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (10.0g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) inMTBE (100 mL) was added TEA (14.46 mL, 48.01 mmol) drop-wise whilestirring. The resulting suspension was stirred at 0° C. for anadditional 30 min and then warmed to ambient temperature. The reactionwas then diluted with water (100 mL), adjusted to pH 4 with 1 NHCl_((aq)). The organic layer was dried (Na₂SO₄), filtered andconcentrated to yield the title compound initially as a yellowish oil,which upon drying overnight under high vacuum became a white solid(12.89 g, 89% yield). ¹H NMR (CDCl₃) δ 7.66 (br s, 1H), 6.98 (s, 2H),2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s, 9H).

Step 2: Preparation of O-(mesitylsulfonyl)hydroxylamine (IntermediateR1, MSH

To TFA (117 mL, 1521 mmol) at 0° C. was slowly added tert-butyl(mesitylsulfonyl)oxycarbamate (39.0 g, 124 mmol) over 25 min. Thereaction mixture was stirred at 0° C. for 1.5 h and then quenched withthe sequential addition of crushed ice (5×ca. 200 mL) and water (2×125mL). The resulting thick suspension was vigorously stirred at ambienttemperature for 5 min. Without allowing the filter cake to run dry, thesolids were collected by careful vacuum filtration followed bysubsequent rinsing with water (4 L) until the filtrate reached pH 6(Caution: explosion risk exists with dry compound at ambienttemperature). The wet filter cake was taken up in DCM (150 mL) and theresulting biphasic solution was separated. The DCM layer was dried overMgSO₄ for 30 min and then filtered and rinsed with DCM (420 mL) toprovide the title compound as a 0.22 M solution in DCM.

Intermediate R2

tert-butyl7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

A solution of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (177mg, 0.835 mmol) and2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100mg, 0.418 mmol) in DMSO (1.4 mL) was heated to 150° C. in a pressuretube overnight. After cooling to ambient temperature the reactionmixture was diluted with EtOAc (30 mL) and washed with brine (3×25 mL).The combined organic extracts were dried over MgSO₄, filtered andconcentrated. The crude residue was purified by silica chromatography(0-100% EtOAc/hexanes) to provide the title compound (91 mg, 53% yield).¹H NMR (CDCl₃) δ 8.51 (d, 1H), 7.80 (dd, 1H), 6.53 (d, 1H), 3.65 (m,2H), 3.59 (m, 2H), 3.45 (s, 2H), 1.47 (s, 9H), 1.32 (s, 12H), 1.00 (m,2H), 0.88 (m, 2H).

The borolane intermediates shown in Table A were prepared according themethod used for the synthesis of Intermediate R2, using the appropriatestarting materials.

TABLE A Intermediate Structure Name Spectral Data R3

tert-butyl (1S,4S)-5-(5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2,5- diazabicyclo[2.2.1]- heptane-2-carboxylate ¹H NMR(CDCl₃) δ 8.50 (s, 1H), 7.79 (d, 1H), 6.29 (d, 1H), 4.98 (br s, 0.6H),4.88 (br s, 0.4H), 4.67 (s, 0.6H), 4.52 (s, 0.4H), 3.35-3.55 (m, 4H),1.93 (d, 2H), 1.46 (s, 4H), 1.41 (s, 5H), 1.32 (s, 12H). R4

tert-butyl 3-(5-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-pyridin-2-yl)-3,8- diazabicyclo[3.2.1]- octane-8-carboxylate ¹H NMR(CDCl₃) δ 8.53 (s, 1H), 7.81 (d, 1H), 6.52 (d, 1H), 4.35 (br m, 2H),3.99 (br m, 2H), 3.11 (br m, 2H), 1.93 (m, 2H), 1.74 (m, 2H), 1.48 (s,9H), 1.32 (s, 12H). R5

tert-butyl ((1R,3s,5S)-8- (5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-8- azabicyclo[3.2.1]octan- 3-yl)carbamate ¹H NMR(CDCl₃) δ 8.53 (s, 1H), 7.80 (d, 1H), 6.59 (d, 1H), 4.57 (m, 2H), 4.07-4.20 (m, 2H), 2.07 (m, 2H), 1.89 (m, 4H), 1.50 (m, 2H), 1.40 (s, 9H),1.32 (s, 12H). R6

1-(5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin- 4-ol ¹H NMR (CDCl₃) δ 8.53 (s, 1H), 7.80 (d,1H), 6.59 (d, 1H), 4.57 (m, 2H), 4.07- 4.20 (m, 2H), 2.07 (m, 2H), 1.89(m, 4H), 1.50 (m, 2H), 1.40 (s, 9H), 1.32 (s, 12H). R7

(1R,3r,5S)-8-(5-(4,4,5,5- tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2- yl)-8-azabicyclo-[3.2.1]- octan-3-ol ¹H NMR(CDCl₃) δ 8.53 (d, 1H), 7.78 (dd, 1H), 6.48 (d, 1H), 4.52 (s, 2H), 4.04(s, 1H), 2.31 (m, 2H), 2.18 (dt, 2H), 2.06 (m, 1H), 1.69 (d, 2H), 1.31(s, 12H). R8

tert-butyl (1-(5-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-pyridin-2-yl)piperidin- 4-yl)carbamate ¹H NMR (CDCl₃) δ 8.52 (s, 1H),7.79 (d, 1H), 6.60 (d, 1H), 4.46 (br s, 1H), 4.30 (m, 2H), 3.71 (br s,1H), 3.01 (t, 2H), 2.01 (m, 2H, 1.45 (s, 9H), 1.38 (m, 2H), 1.32 (s,12H).

Intermediate R9

tert-butyl((1R,3r,5S)-8-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate

A solution of tert-butyl(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ylcarbamate (378 mg, 1.67 mmol)and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(200 mg, 0.835 mmol) in DMSO (3 mL) was stirred at 150° C. in a pressuretube for 3 d. After cooling to ambient temperature the reaction mixturewas diluted with water (10 mL) and the resulting suspension wasfiltered, rinsed with water and dried in vacuo to provide the titlecompound (228 mg, 64% yield). ¹H NMR (CDCl₃) δ 8.53 (dd, 1H), 7.79 (dd,1H), 6.48 (d, 1H), 4.96 (br s, 1H), 4.55 (br s, 2H), 3.75 (br s, 1H),2.14-2.27 (m, 4H), 2.01 (m, 2H), 1.67 (d, 2H), 1.44 (s, 9H), 1.32 (s,12H).

Intermediate R10

tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylateStep 1: Preparation of tert-butyl4-(4-bromophenyl)piperidine-1-carboxylate

At ambient temperature, a suspension of 4-(4-bromophenyl)piperidine(1000 mg, 4.164 mmol) in DCM (20 mL) was treated with DIEA (1451 μL,8.328 mmol) followed by Boc-anhydride (1064 μL, 4.581 mmol), and thenstirred overnight. The reaction mixture was subsequently diluted withwater (50 mL) and then extracted with DCM (3×50 mL). The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuoto afford the title compound (1363 mg, 96% yield). ¹H NMR (CDCl₃) δ 7.42(m, 2H), 7.07 (m, 2H), 4.24 (m, 2H), 2.79 (dt, 2H), 2.61 (tt, 1H), 1.79(m, 2H), 1.58 (qd, 2H), 1.48 (s, 9H).

Step 2: Preparation of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate

In a pressure tube a solution of tert-butyl4-(4-bromophenyl)piperidine-1-carboxylate (1363 mg, 4.006 mmol) indioxane was treated with bis(pinacolato)diboron (1526 mg, 6.009 mmol),KOAc (1179 mg, 12.02 mmol), and PdCl₂(dppf).DCM (327.1 mg, 0.4006 mmol).The mixture was sparged with nitrogen for 1 min and then sealed andheated at 100° C. overnight. After cooling to ambient temperature, thereaction mixture was diluted with a mixture of EtOAc (75 mL)/water (50mL)/brine (25 mL), and the resulting emulsion was filtered throughCelite® and rinsed with EtOAc. The biphasic filtrate was separated andthe organic phase was washed with brine and then dried (MgSO₄), filteredand concentrated in vacuo. The crude residue was purified by silicachromatography (0-50% EtOAc/hexanes) to afford the title compound (1437mg, 93% yield). ¹H NMR (CDCl₃) δ 7.76 (d, 2H), 7.22 (m, 2H), 4.24 (d,2H), 2.79 (dt, 2H), 2.65 (tt, 1H), 1.81 (m, 2H), 1.63 (dq, 2H), 1.48 (s,9H), 1.33 (s, 12H).

Intermediate R11

3,3-dimethyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)butan-1-one

To a mixture of1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (850mg, 2.95 mmol) and TEA (1233 μL, 8.85 mmol) in DCM (10 mL) was added3,3-dimethylbutanoyl chloride (486 μL, 3.54 mmol). The reaction wasstirred overnight at ambient temperature and subsequently quenched withMeOH (1 mL), concentrated in vacuo, taken up in water (5 mL) andsonicated. The solid was collected by filtration, washed with water (2mL) and hexanes (3×5 mL) to afford the title compound (938 mg, 82%yield).

Intermediate P17

6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP4; 0.200 g, 0.793 mmol) in DCE (7.93 mL) was treated with AlCl₃ (0.529g, 3.97 mmol), then stirred at 80° C. for 2 h. After cooling to roomtemperature, the reaction mixture was quenched with water (100 mL), andextracted with DCM. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica chromatography (0-75% EtOAc/Hexanes as the gradienteluent) to cleanly afford the title compound (78.6 mg, 42% yield). MS(apci) m/z=237.9 (M+H).

Intermediate P18

4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP17; 1.00 g, 4.20 mmol) in dioxane (42.0 mL) was treated with1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.98 g, 6.30 mmol) and 2 M aqueous K₂CO₃ (4.20 mL, 8.402 mmol), thensparged with N₂ for 5 min. The reaction mixture was treated with XPhos(0.401 g, 0.842 mmol) and Pd₂(dba)₃ (0.192 g, 0.210 mmol), then spargedwith N₂ for 5 min, sealed and stirred overnight at 80° C. After coolingto room temperature, the reaction mixture was diluted with water, andextracted with EtOAc. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel (Biotage Isolera, 80 g, Isco RediSep, 0-10% MeOHin DCM as the gradient eluent) to afford the title compound (1.06 g, 73%yield).

Intermediate P19

3-cyano-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

A room temperature solution of4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P18; 1.057 g, 3.061 mmol) in DCM (15.3 mL) was treatedwith1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.187 g, 6.121 mmol) and DIEA (1.6 mL, 9.2 mmol). The reaction mixturewas stirred overnight at room temperature, and then quenched with water.The resulting biphasic mixture was extracted with DCM. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(0-50% DCM/EtOAc as the gradient eluent) to afford the title compound(958 mg, 66% yield).

Intermediate P20

6-(1,5-dimethyl-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP17; 0.250 g, 1.05 mmol) in dioxane (10.5 mL) was treated with1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.350 g, 1.58mmol) and 2M aqueous K₂CO₃ (1.10 mL, 2.10 mmol), then sparged with N₂for 5 min. The reaction mixture was treated with XPhos (0.100 g, 0.210mmol) and Pd₂(dba)₃ (0.0481 g, 0.0525 mmol), then sparged with N₂ for 5min, sealed, and stirred overnight at 80° C. After cooling to roomtemperature, the reaction mixture was diluted with water, and extractedwith EtOAc. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. 1:1 DCM and hexanes wereadded to the crude material and the solids were filtered to afford thetitle compound (0.135 g, 51% yield). MS (apci) m/z=254.1 (M+H).

Intermediate P21

3-cyano-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

A room temperature solution of6-(1,5-dimethyl-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P20; 0.135 g, 0.533 mmol) in DCM (2.67 mL) was treatedwith1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(0.209 g, 0.586 mmol) and DIEA (0.186 mL, 1.07 mmol). The reactionmixture was stirred overnight at room temperature, and then quenchedwith water. The resulting biphasic mixture was extracted with DCM. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (0-50% DCM/EtOAc as the gradient eluent) to afford thetitle compound (125 mg, 61% yield). MS (apci) m/z=386.0 (M+H).

Intermediate P22

6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP17; 0.250 g, 1.05 mmol) in dioxane (10.5 mL) was treated with1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.350 g, 1.58mmol) and 2 M aqueous K₂CO₃ (1.10 mL, 2.10 mmol), then sparged with N₂for 5 min. The reaction mixture was treated with XPhos (0.100 g, 0.210mmol) and Pd₂(dba)₃ (0.0481 g, 0.0525 mmol), then sparged with N₂ for 5min, sealed and stirred overnight at 80° C. After cooling to roomtemperature, the reaction mixture was diluted with water, and extractedwith EtOAc. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. 1:1 DCM and hexanes wereadded to the crude material and the solids were filtered to afford thetitle compound (0.192 g, 72% yield). MS (apci) m/z=254.1 (M+H).

Intermediate P23

3-cyano-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

A room temperature solution of6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P22; 0.192 g, 0.757 mmol) in DCM (3.79 mL) was treatedwith1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(0.298 g, 0.833 mmol) and DIEA (0.264 mL, 1.51 mmol). The reactionmixture was stirred overnight at room temperature, and then quenchedwith water. The resulting biphasic mixture was extracted with DCM. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (0-50% DCM/EtOAc as the gradient eluent) to afford thetitle compound (189 mg, 65% yield). MS (apci) m/z=386.0 (M+H).

Intermediate P24

3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

A room temperature solution of4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(Intermediate P7, step 1; 1.90 g, 8.32 mmol) and PPTS (0.209 g, 0.832mmol) in DCM (20 mL) was treated with NIS (1.97 g, 8.74 mmol) thenstirred overnight at room temperature. The reaction mixture was dilutedwith DCM, and washed with 2 N aqueous NaOH. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica chromatography (0-50% EtOAc inHexanes as the gradient eluent) to afford the title compound (2.4 g, 81%yield). MS (apci) m/z=355.0 (M+H).

Intermediate P25

4-methoxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

A mixture of3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(Intermediate P24; 2.4 g, 6.78 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.84 mL, 20.3 mmol),PdCl₂(dppf).CH₂Cl₂ (0.553 g, 0.678 mmol), and K₂CO₃ (4.68 g, 33.9 mmol)in DMF (67.8 mL) was sparged with Argon, then sealed and stirred for 18h at 100° C. The reaction mixture was diluted with water (60 mL) andextracted with EtOAc (3×100 mL). The combined organic extracts weredried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica chromatography (using 50-100% EtOAc inHexanes as the gradient eluent) and then by reverse phase HPLC (5-95%water/ACN with 0.1% TFA as the gradient eluent) to afford the titlecompound (500 mg, 31% yield). MS (apci) m/z=243.1 (M+H).

Intermediate P26

3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol

A room temperature solution of4-methoxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(Intermediate P25; 500 mg, 2.06 mmol) in DCE (20.6 mL) was treated withAlCl₃ (1.38 g, 10.3 mmol), then stirred for 2 h at 80° C. After coolingto room temperature, the reaction mixture was quenched with water (100mL), and extracted with 20% iPrOH in DCM. The combined organic extractswere dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo tocleanly afford the title compound (390 mg, 83% yield). MS (apci)m/z=229.1 (M+H).

Intermediate P27

3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

A room temperature solution of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-ol(Intermediate P26; 0.390 g, 1.71 mmol) in DCM (17.1 mL) was treated withDIEA (0.613 mL, 3.42 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(0.671 g, 1.88 mmol). The reaction mixture was stirred for 5 d at roomtemperature. The reaction mixture was purified directly by silicachromatography (25-75% EtOAc/Hexanes as the gradient eluent) to affordthe title compound (400 mg, 65% yield). MS (apci) m/z=361.0 (M+H).

Intermediate R12

(R)-3-hydroxy-2-phenylpropanoic acid Step 1: Preparation of(S)-4-benzyl-3-(2-phenylacetyl)oxazolidin-2-one

A solution of (S)-(−)-4-benzyl-2-oxazolidinone (1.34 g, 7.57 mmol) inTHF (100 mL) was cooled to −78° C. then treated with 1.0 M lithiumbis(trimethylsilyl)amide in THF (7.95 mL, 7.95 mmol). The reactionmixture was stirred for 30 min at −78° C., then stirred 16 h at roomtemperature, before quenching with water. The resulting biphasic mixturewas extracted with EtOAc. The combined organic extracts were washed withwater and brine, then dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(5-60% Hexanes-EtOAc as the gradient eluent) to cleanly afford the titlecompound (1.55 g, 69% yield). MS (apci) m/z=252 [(M-C02)+1].

Step 2: Preparation of(S)-4-benzyl-3-((R)-3-hydroxy-2-phenylpropanoyl)oxazolidin-2-one

A room temperature solution of(S)-4-benzyl-3-(2-phenylacetyl)oxazolidin-2-one (step 1; 1.55 g, 5.25mmol) in DCM (50 mL) was sparged with N₂, then cooled to 0° C. Theresulting degassed solution was treated with titanium (IV) chloride(0.604 mL, 5.51 mmol), and stirred for 5 min at 0° C., before treatingwith DIEA (1.01 mL, 5.77 mmol). The resulting mixture was stirred for 1h at 0° C., then treated sequentially with 0.60 M 1,3,5-trioxane in DCM(10 mL, 6.04 mmol) and additional titanium (IV) chloride (0.604 mL, 5.51mmol). The reaction mixture was stirred for an additional 4 h at 0° C.,before quenching with saturated NH₄Cl. The resulting biphasic mixturewas extracted with DCM. The combined organic extracts were washed withwater, then dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica chromatography (5-50%DCM-Acetone as the gradient eluent) to cleanly afford the title compound(1.22 g, 71% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.34-7.23 (m, 10H),5.20-5.14 (m, 2H), 4.74-4.70 (m, 1H), 4.28-4.24 (t, 1H), 4.16-4.08 (m,2H), 3.61-3.56 (m, 1H), 3.06-2.96 (m, 2H).

Step 3: Preparation of (R)-3-hydroxy-2-phenylpropanoic acid

A cold (0° C.) solution of(S)-4-benzyl-3-((R)-3-hydroxy-2-phenylpropanoyl)oxazolidin-2-one (step2; 1.22 g, 3.75 mmol) in THF (40 mL) was treated sequentially with 30%(w/w) aqueous H₂O₂ (3.60 mL, 37.5 mmol) and 2 M aqueous LiOH in (3.75mL, 7.50 mmol). The resulting reaction mixture was stirred for 2 h atroom temperature. The reaction mixture was treated with 2 M aqueous KOH(3.75 mL, 7.50 mmol), and refluxed for 2 h. After cooling to roomtemperature, the reaction mixture was treated with 1 M aqueous Na₂SO₃ (5mL), before concentrating in vacuo to remove the volatile organics. Theresulting aqueous residue was diluted with Et₂O, and washed with 1 Maqueous NaOH. The aqueous extracts were acidified to pH 2 using 4 Maqueous HCl, and extracted with 4:1 DCM/iPrOH. The combined DCM/iPrOHextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by C18 reverse phase chromatography(5-95% water/ACN with 0.1% TFA as the gradient eluent) to cleanly affordthe title compound (355.6 mg, 57% yield). ¹H NMR (400 MHz, DMSO-d₆) δ12.34 (s, 1H), 7.34-7.23 (m, 5H), 3.93-3.89 (t, 1H), 3.65-3.54 (m, 2H).

Intermediate R13

tert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)azetidine-1-carboxylateStep 1: Preparation of tert-butyl3-(5-bromopyridin-2-yl)azetidine-1-carboxylate

A room temperature suspension of zinc dust (<10 um, 98+%; 0.353 g, 5.40mmol) in THF (10 mL) was treated with 1,2-dibromoethane (0.0310 mL,0.360 mmol) and chlorotrimethylsilane (0.0457 mL, 0.360 mmol) thenstirred for 15 min at 60° C. The resulting mixture was treated with asolution of tert-butyl 3-iodoazetidine-1-carboxylate (1.02 g, 3.60 mmol)in DMA (10 mL), and stirred an additional 15 min at 60° C. beforecooling to room temperature. The reaction mixture was treated with2,5-dibromopyridine (0.896 g, 3.78 mmol), PdCl₂(dppf).CH₂Cl₂ (0.147 g,0.180 mmol), and CuI (0.0343 g, 0.180 mmol), sparged with Argon, sealed,and stirred 16 h at 80° C. The reaction mixture was cooled to roomtemperature, diluted with EtOAc and water, and then filtered. Thefiltrate was diluted with additional EtOAc, and washed with water andbrine. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicachromatography (5-70% Hexanes-EtOAc as the gradient eluent) to cleanlyafford the title compound (357.6 mg, 32% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.72-8.71 (m, 1H), 8.01-7.98 (m, 1H), 7.34-7.31 (m, 1H),4.19-4.15 (m, 2H), 3.96-3.87 (m, 3H), 1.39 (s, 9H).

Step 2: Preparation of tert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)azetidine-1-carboxylate

A room temperature solution of tert-butyl3-(5-bromopyridin-2-yl)azetidine-1-carboxylate (step 1; 153.5 mg, 0.4901mmol) in dioxane (4.9 mL) was treated with bis(pinacolato)diboron (136.9mg, 0.5391 mmol), PdCl₂(dppf).CH₂Cl₂ (40.02 mg, 0.04901 mmol), andCH₃CO₂K (144.3 mg, 1.470 mmol). The resulting mixture was sparged withArgon, sealed, and stirred 16 h at 100° C. before cooling to roomtemperature. The reaction mixture was diluted with EtOAc, and washedwith water and brine. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford thetitle compound (176.0 mg, 99.7% yield). MS (apci) m/z=279.1; (M(BOH)+1).

The compounds in Table DD were prepared according to the methoddescribed for Intermediate R13, replacing tert-butyl3-iodoazetidine-1-carboxylate with the appropriate alkyl iodide inStep 1. Reactions were monitored by LCMS, and reaction times wereadjusted accordingly. Products were purified as in Intermediate R13utilizing the appropriate gradient eluent in chromatography to cleanlyafford the title compounds.

TABLE DD MS (apci) Intermediate Structure Chemical Name m/z R14

tert-butyl 3-(5-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-pyridin-2-yl)pyrrolidine- 1-carboxylate 293.1 R15

tert-butyl 3-(5-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-pyridin-2-yl)piperidine- 1-carboxylate 388.1

Intermediate R16

1-(5-boronopyridin-2-yl)-4-ethylpiperidine-4-carboxylic acid

A room temperature solution of2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 g,9.0 mmol) in DMSO (18 mL) was treated with4-ethylpiperidine-4-carboxylic acid (4.7 g, 30 mmol) and K₂CO₃ (5.0 g,36 mmol), then stirred overnight at 80° C. After cooling to roomtemperature, the reaction mixture was diluted with water, and theresulting mixture was extracted with 20% MeOH/DCM. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford the title compound containing impurities (4.2 g,quantitative yield). The material was used without further purification.MS (apci) m/z=279.1 (M+H).

Intermediate R17

(6-(4-ethyl-4-(isopropylcarbamoyl)piperidin-1-yl)pyri din-3-yl)boronicacid

A room temperature solution of1-(5-boronopyridin-2-yl)-4-ethylpiperidine-4-carboxylic acid(Intermediate R16; 2.45 g, 8.81 mmol) in DMA (35.2 mL) was treated withDIEA (8.44 mL, 48.5 mmol), propan-2-amine (2.25 mL, 26.4 mmol), and HATU(8.37 g, 22.0 mmol), then allowed to stir overnight at room temperature.The reaction mixture was diluted with water and extracted with 20%MeOH/DCM. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The crude material waspurified by C18 reverse phase chromatography (0-80% ACN/water as thegradient eluent) to afford the title compound (1.0 g, 36% yield). MS(apci) m/z=320.2 (M+H).

Intermediate R18

(S)-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)boronicacid

A room temperature solution of (6-(piperazin-1-yl)pyridin-3-yl)boronicacid (1.5 g, 7.25 mmol) in DMA (36.2 mL) was treated with DIEA (5.05 mL,29.0 mmol) and stirred for 20 min at room temperature and then treatedwith 4-nitrophenyl carbonochloridate (2.92 g, 14.5 mmol). The resultingmixture was stirred overnight at room temperature. DIEA (5 mL, 29.0mmol) and (S)-3-methoxypyrrolidine (3.66 g, 36.2 mmol) were added, andthe reaction mixture was stirred for 48 h at room temperature. Thereaction mixture was diluted with water and extracted with 20% MeOH/DCM.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by C18reverse phase chromatography (0-40% ACN/water as the gradient eluent) toafford the title compound (1.0 g, 41% yield). MS (apci) m/z=335.1 (M+H).

Intermediate R19

1-ethyl-3-vinyl-1H-pyrazole

A room temperature solution of 1-ethyl-3-iodopyrazole (2.52 g, 11.4mmol) in 4:1 dioxane/water (100 mL) was treated with potassiumvinyltrifluoroborate (1.67 g, 12.5 mmol), XPhos (0.107 g, 0.225 mmol)and Pd₂(dba)₃ (0.0516 g, 0.0563 mmol), then sparged with Argon, sealed,and stirred 16 h at 100° C. After cooling to room temperature, thereaction mixture was diluted with water, extracted with DCM, andfiltered. The filtrate was diluted with additional DCM, and washed withwater. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicachromatography (5-70% Hexanes-EtOAc as the gradient eluent) to affordthe title compound (689.1 mg, 50% yield). MS (apci) m/z=123.1 (M+H).

Intermediate R20

1,3-diethyl-1H-pyrazole

A room temperature solution of 1-ethyl-3-vinyl-1H-pyrazole (IntermediateR19; 689.1 mg, 5.641 mmol) in MeOH (28 mL) was treated with 10% Pd/C(600.3 mg, 0.2820 mmol). The resulting mixture was sparged with N2 andthen with H₂ for several minutes, then stirred under an atmosphere of H₂for 16 h at ambient temperature and pressure. The resulting mixture wasfiltered through GF/F paper and the filtrate was concentrated in vacuoto afford the title compound (453.3 mg, 65% yield). MS (apci) m/z=125.2(M+H).

Intermediate R21

4-bromo-1,3-diethyl-1H-pyrazole

A room temperature solution of 1,3-diethyl-1H-pyrazole (IntermediateR20; 390.2 mg, 3.142 mmol) in ACN (30 mL) was treated with NBS (559.2mg, 3.142 mmol), then stirred for 16 h at room temperature. The reactionmixture was concentrated in vacuo. The residue was purified by silicachromatography (5-50% Hexanes-EtOAc as the gradient eluent) to affordthe title compound (418.2 mg, 66% yield). MS (apci) m/z=203.0 (M+H). ¹HNMR (400 MHz, DMSO-d₆) δ 7.86 (s, 1H), 4.07-4.01 (q, 2H), 2.52-2.47 (q,2H), 1.34-1.30 (t, 3H), 1.16-1.12 (t, 3H).

Intermediate R22

1-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A −78° C. solution of 4-bromo-1-ethyl-3-methyl-1H-pyrazole (404.4 mg,2.139 mmol) in THF (21 mL) was treated dropwise with 2.5 M n-BuLi inhexanes (1198 μL, 2.995 mmol). The resulting mixture was stirred for 30min at −78° C., then treated with2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (916.4 μL, 4.492mmol). The reaction mixture was stirred for 30 min at room temperature,and then treated with saturated NH₄Cl. The biphasic mixture wasextracted with EtOAc, and the combined organic extracts were washed withbrine. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicachromatography (5-70% Hexanes-EtOAc as the gradient eluent) to affordthe title compound (324.5 mg, 64% yield). ¹H NMR (400 MHz, DMSO-d₆) δ7.77 (s, 1H), 4.05-3.99 (q, 2H), 2.21 (s, 3H), 1.33-1.29 (t, 3H), 1.23(s, 12H).

The compounds in Table EE were prepared according to the methoddescribed for Intermediate R22, replacing4-bromo-1-ethyl-3-methyl-1H-pyrazole with the appropriate commerciallyavailable bromopyrazole (except where noted). Reactions were monitoredby LCMS, and reaction times were adjusted accordingly. Products werepurified as in Intermediate R22 utilizing the appropriate gradienteluent in chromatography to cleanly afford the title compounds.

TABLE EE Intermediate # Structure Chemical Name Spectral data R23

3-ethyl-1-methyl-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole ¹H NMR (400 MHz, CDCl₃) □□ =7.53 (s, 1 H), 3.80 (s, 3H), 2.76 (q, 2 H), 1.28 (s, 12 H), 1.22 (t, 3 H) R24

1-isopropyl-3-methyl- 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole MS (apci) m/z = 251.2 (M + H) R25

1-(tert-butyl)-3-methyl- 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole MS (apci) m/z = 265.2 (M + H)  R26*

1,3-diethyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole MS (apci) m/z = 251.2 (M + H) *prepared from Intermediate R21

Intermediate R27

tert-butyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperazine-1-carboxylate

A room temperature solution of tert-butyl4-(6-chloropyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.336 mmol) indioxane (4 mL) was treated with bis(pinacolato)diboron (93.8 mg, 0.369mmol), Pd(OAc)₂ (9.05 mg, 0.0403 mmol), X-Phos (28.8 mg, 0.0604 mmol),and KOAc (98.9 mg, 1.01 mmol). The resulting mixture was sparged withArgon, sealed, and stirred overnight at 90° C. before cooling to roomtemperature. The reaction mixture was concentrated in vacuo and thecrude product was used in the next step without purification, assumingquantitative yield. MS (apci) m/z=208 (M(B(OH)₂—BOC).

Preparation of Synthetic Examples Example 1

tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

To a mixture of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 10.0 g, 26.9 mmol) andtert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(12.6 g, 32.3 mmol) in dioxane (250 mL) was added 2 M Na₂CO_(3(aq))(14.3 g, 135 mmol), and the reaction mixture was sparged with nitrogenfor 15 min before introducing Pd₂(dba)₃ (1.23 g, 1.35 mmol) and X-Phos(2.57 g, 5.39 mmol). The mixture was sparged with nitrogen for anadditional 5 min and then heated at 80° C. overnight. After cooling toambient temperature, the reaction mixture was poured into H₂O (1.5 L)and stirred for 2 h. The resulting suspension was filtered and rinsedsequentially with H₂O (3×200 mL), MTBE (4×100 mL) and hexanes (4×100mL), yielding the title compound as a solid after drying in vacuoovernight (12 g, 92% yield). MS (apci) m/z=485.2 (M+H).

Example 2

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution of tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 1, 12.0 g, 24.77 mmol) in MeOH (12 mL) and DCM (50 mL) wasadded HCl (5-6M in iPrOH, 49.53 mL, 247.7 mmol). After stirring atambient temperature for 21 h the reaction was diluted with MeOH (50 mL)and DCM (50 mL). The suspension was stirred at ambient temperature untilLCMS indicated the reaction was complete. The reaction mixture wasfiltered, rinsed with Et₂O (5×50 mL) and then dried for 19 h in a 45° C.vacuum oven to yield the title compound (9.97 g, 88% yield). MS (apci)m/z=385.1 (M+H).

Example 2a

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of tert-Butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 1, 1.26 g, 2.60 mmol) in 20% MeOH/DCM (50 mL) was added 4 N HClin dioxane (10 mL). The resulting mixture was stirred overnight and thentreated with water and extracted with 20% MeOH/DCM (3×50 mL). Afterphase-separation, the combined organic extracts and the aqueous layerwere further treated independently. The aqueous layer was treated withsaturated NaHCO_(3(aq)), and the resulting suspension was vacuumfiltered and rinsed with water and hexanes to provide the title compound(600 mg). The combined organic extracts from the reaction were washedwith saturated NaHCO_(3(aq)), then dried (Na₂SO₄), filtered andconcentrated in vacuo to provide a second batch of the title compound(243 mg). The two batches of product were combined to provide the titlecompound (843 mg, 84% yield). MS (apci) m/z=385.1 (M+H).

Example 3

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(3-(methylsulfonyl)propanoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

3-(Methylsulfonyl)propanoic acid (12 mg, 0.078 mmol) and HATU (30 mg,0.078 mmol) were dissolved in DMA (325 μL) at ambient temperature. After25 min,6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 2a, 25 mg, 0.065 mmol) was added in one portion followed byaddition of DIEA (34 μL, 0.20 mmol). After stirring overnight at ambienttemperature the resulting suspension was vacuum filtered and the solidswere rinsed successively with ice-cold MeOH (1 mL) and Et₂O (3 mL) toprovide the title compound (18 mg, 52% yield). MS (apci) m/z=519.0(M+H).

Example 4

((S)-4-(6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(S)-2-Hydroxy-3-phenylpropanoic acid (8.18 mg, 0.0492 mmol) and HATU(18.7 mg, 0.0492 mmol) were dissolved in DMA (164 μL) at ambienttemperature. After 25 min,6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2, 15 mg, 0.033 mmol) was added in one portionfollowed by DIEA (29 μL, 0.16 mmol). The reaction was stirred overnightat ambient temperature and then directly purified by reverse phasechromatography (5-50% ACN/water) to provide the title compound (16.8 mg,94% yield). MS (apci) m/z=533.1 (M+H).

The compounds in the Table B were prepared in a similar fashion asdescribed for the syntheses of Examples 3 and 4, replacing3-(methylsulfonyl)propanoic acid or (S)-2-hydroxy-3-phenylpropanoic acidwith the appropriate acid starting material.

TABLE B MS (apci) Ex# Structure Chemical Name m/z 5

6-(1-methyl-1H- pyrazol-4-yl)-4- (6-(4-(2-(pyridin- 2-yl)acetyl)piperazin-1-yl) pyridin-3-yl) pyrazolo[1,5- a]pyridine-3- carbonitrile504.1 (M + H) 6

(S)-4-(6-(4-(2- hydroxy-2- phenylacetyl) piperazin-1-yl) pyridin-3-yl)-6-(1-methyl- 1H-pyrazol- 4-yl)pyrazolo [1,5-a]pyridine- 3-carbonitrile519.1 (M + H) 7

(R)-4-(6-(4-(3- hydroxy-3- phenylpropanoyl) piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 533.1 (M + H) 8

(S)-4-(6-(4-(3- hydroxy-3- phenylpropanoyl) piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 533.1 (M + H) 9

(R)-4-(6-(4-(2- hydroxy-3- phenylpropanoyl) piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 533.1 (M + H) 10

4-(6-(4-(2-(2- fluorophenyl)-2- hydroxyacetyl) piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 537.2 (M + H) 11

4-(6-(4- ((1S,3S)-3- hydroxycyclo- pentane-1- carbonyl) piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 497.1 (M + H) 12

4-(6-(4- ((1S,3R)-3- hydroxycyclo- pentane-1- carbonyl) piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 497.1 (M + H) 13

(S)-4-(6-(4- (3,3-difluoro- cyclopentane- 1-carbonyl) piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 517.1 (M + H) 14

(R)-6-(1- methyl-1H- pyrazol-4-yl)- 4-(6-(4-(2- phenyl- propanoyl)piperazin-1-yl) pyridin-3-yl) pyrazolo[1,5- a]pyridine-3- carbonitrile517.1 (M + H) 15

(S)-6-(1-methyl- 1H-pyrazol-4- yl)-4-(6-(4-(2- phenylpropanoyl)piperazin-1-yl) pyridin-3-yl) pyrazolo[1,5- a]pyridine-3- carbonitrile517.2 (M + H) 16

4-(6-(4-(3- hydroxy-2- phenylpropanoyl) piperazin-1-yl) pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3- carbonitrile533.1 (M + H) 17

(S)-tert-butyl (3-(4-(5-(3- cyano-6-(1- methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl) pyridin-2-yl) piperazin-1-yl)- 3-oxo-1-phenylpropyl) carbamate 632.1 (M + H) 18

tert-butyl tert-butyl(2-(4- (5-(3-cyano-6- (1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl) pyridin-2-yl) piperazin-1-yl)- 2-oxoethyl)carbamate 598.2 (M + H) 19

6-(1-methyl-1H- pyrazol-4-yl)- 4-(6-(4-(2-(6- methylpyridin-3-yl)acetyl) piperazin-1-yl) pyridin-3-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 518.1 (M + H) 20

6-(1-methyl-1H- pyrazol-4-yl)-4- (6-(4-(2-(1- methyl-1H- pyrazol-5-yl)acetyl) piperazin-1-yl) pyridin-3-yl) pyrazolo[1,5- a]pyridine-3-carbonitrile 507.1 (M + H) 21

4-(6-(4- (cyclopentane- carbonyl) piperazin-1-yl) pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl) pyrazolo[1,5- a]pyridine-3- carbonitrile481.2 (M + H)

Example 22

4-(6-(4-(2-(tert-butylamino)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution oftert-butyl(2-(4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)carbamate(Example 18, 10 mg, 0.017 mmol) in DCM (0.1 mL) was added 5 M HCl iniPrOH (167 μL, 0.84 mmol) and the reaction mixture was stirred atambient temperature for 1 h. The reaction mixture was then concentratedin vacuo to afford the title compound (9 mg, 93% yield). MS (apci)m/z=498.2 (M+H).

Example 23

(S)-4-(6-(4-(3-amino-3-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution of (S)-tert-butyl(3-(4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-3-oxo-1-phenylpropyl)carbamate(Example 17, 18 mg, 0.028 mmol) in DCM (0.1 mL) was added 5 M HCl iniPrOH (285 μL, 1.4 mmol) and the reaction mixture was stirred at ambienttemperature for 1 h. The reaction mixture was then concentrated in vacuoto afford the title compound (17 mg, 98% yield). MS (apci) m/z=532.2(M+H).

Example 24

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(1-phenylcyclopentanecarbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

1-Phenylcyclopentanecarboxylic acid (12.5 mg, 0.0656 mmol) and HATU(24.9 mg, 0.0656 mmol) were dissolved in DMA (273 μL) at ambienttemperature and the reaction mixture was stirred for 25 min, followed byaddition of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (25 mg, 0.0547 mmol) and DIEA (47.6 μL, 0.273 mmol),each in one portion. After overnight stirring the resulting suspensionwas diluted with EtOAc (0.5 mL) and vacuum filtered and rinsedsuccessively with EtOAc (3×0.5 mL) and Et₂O (1 mL) to provide the titlecompound as a white solid (21 mg, 68% yield). MS (apci) m/z=557.2 (M+H).

The compounds in Table C were prepared according the method used for thesynthesis of Example 24, replacing 1-phenylcyclopentanecarboxylic acidwith the appropriate acid starting material.

TABLE C MS (apci) Ex# Structure Chemical Name m/z 25

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(1- phenylcyclopropane-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 529.1 (M + H) 26

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(2-methyl-2- phenylpropanoyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile531.2 (M + H) 27

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(1- phenylcyclobutane-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 543.2 (M + H) 28

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(1- phenylcyclohexane-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 571.2 (M + H) 29

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(3-methyl- 2-phenylbutanoyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile545.2 (M + H)

Example 30

(S)-4-(6-(4-(2-hydroxypropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.030 g, 0.0780 mmol) and L-(+)-Lactic acid (0.00729 mL, 0.0975 mmol)in DMF (2.60 mL) was added HATU (0.0386 g, 0.101 mmol). The reactionmixture was stirred for 24 h at ambient temperature and then quenchedwith water (10 mL). The reaction mixture was then extracted with EtOAc(3×15 mL) and the combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica chromatography (0-7% of a 5% NH₄OH in MeOH/DCM) toprovide the title compound (0.010 g, 28% yield). MS (apci) m/z=457.2(M+H).

The compounds in Table D were prepared and purified according the methodused for the synthesis of Example 30, replacing L-(+)-Lactic acid withthe appropriate acid starting material.

TABLE D MS (apci) Ex# Structure Chemical Name m/z 31

4-(6-(4-(2-hydroxy- 2-methylpropanoyl) piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 471.2 (M + H) 32

(R)-4-(6-(4-(2- hydroxypropanoyl) piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 457.2 (M + H)

Example 33

4-(6-(4-(3-(dimethylamino)propanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

To a mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (30 mg 0.066 mmol) in DCM (1 mL) at ambient temperaturewas sequentially added N-methylmorpholine (14 □L, 0.13 mmol),3-(dimethylamino)propanoic acid (9.2 mg, 0.079 mmol), and HATU (25 mg,0.066 mmol). The reaction mixture was stirred at ambient temperature for12 h, and then concentrated and purified by reverse-phase preparativeHPLC (10 to 80% acetonitrile/water with 0.1 v/v % TFA) to yield thetitle compound (17 mg, 36% yield). MS (apci) m/z=484.2 (M+H).

The compounds in Table E were prepared according the method describedfor the synthesis of Example 33, replacing 3-(dimethylamino)propanoicacid with the appropriate acid starting material, and utilizingreverse-phase preparative HPLC (10 to 80% acetonitrile/water with 0.1v/v % TFA or 0.04 v/v % NH₄OH) to yield purified title compounds as TFAsalts unless otherwise stated.

TABLE E MS (apci) Ex# Structure Chemical Name m/z 34

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4- pivaloylpiperazin-1-yl)pyridin-3-yl) pyrazolo[1,5-a]pyridine- 3-carbonitrile 2,2,2-trifluoroacetate 469.2 (M + H) 35

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(1-methyl- 1H-pyrazole-4-carbonyl)piperazin-1- yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 2,2,2- trifluoroacetate 493.1 (M + H) 36

4-(6-(4-(1-methyl-1H- imidazole-4- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate) 493.2 (M + H) 37

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(5- methylisoxazole-3-carbonyl)piperazin-1- yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 2,2,2- trifluoroacetate 494.2 (M + H) 38

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(pyrazine- 2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3- carbonitrile 2,2,2-trifluoroacetate 491.2 (M + H) 39

4-(6-(4-(2-(2,6- difluorophenyl)acetyl) piperazin-l-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 2,2,2- trifluoroacetate 539.2 (M + H) 40

4-(6-(4-(2-methoxyacetyl) piperazin-1-yl)pyridin- 3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3- carbonitrile 2,2,2-trifluoroacetate 457.2 (M + H) 41

4-(6-(4-(1,3-dimethyl- 1H-pyrazole-4- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate 507.2 (M + H) 42

4-(6-(4-(2-(1-methyl- 1H-pyrazol-3-yl) acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate 507.2 (M + H) 43

6-(1-methyl-1H- pyrazol-4-yl)-4-(6- (4-(3-(pyridin-3-yl)propanoyl)piperazin- 1-yl)pyridin-3-yl) pyrazolo[1,5-a] pyridine-3-carbonitrile bis (2,2,2-trifluoroacetate) 518.2 (M + H) 44

(S)-6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(4- prolylpiperazin-1-yl)pyridin-3-yl) pyrazolo[1,5-a] pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 482.1 (M + H) 45

(R)-6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(4- prolylpiperazin-1-yl)pyridin-3-yl) pyrazolo[1,5-a] pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 482.2 (M + H) 46

6-(1-methyl-1H- pyrazol-4-yl)-4-(6- (4-(piperidine-4-carbonyl)piperazin- 1-yl)pyridin-3-yl) pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate) 496.2 (M + H) 47

6-(1-methyl-1H- pyrazol-4-yl)-4-(6- (4-(piperidine-3-carbonyl)piperazin- 1-yl)pyridin-3-yl) pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate) 496.2 (M + H) 48

(R)-4-(6-(4-(2- amino-2-phenylacetyl) piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate) 518.2 (M + H) 49

6-(1-methyl-1H- pyrazol-4-yl)-4- (6-(4-(5- methylpyrazine-2-carbonyl)piperazin-1- yl)pyridin-3-yl) pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate) 505.1 (M + H) 50

(S)-4-(6-(4-(2-amino- 2-phenylacetyl) piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate) 518.2 (M + H) 51

4-(6-(4-(2,6- difluorobenzoyl) piperazin-1-yl) pyridin-3-yl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile2,2,2-trifluoroacetate 525.1 (M + H) 52

4-(6-(4-(4-(dimethyl- amino)butanoyl) piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2- trifluoroacetate) 498.2 (M + H)

Example 53

(R)-4-(6-(4-(2-hydroxy-4-methylpentanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(25 mg, 0.065 mmol) in DMF (2.17 mL) was added DIEA (0.0114 mL, 0.065mmol), (R)-2-hydroxy-4-methylpentanoic acid (8.6 mg, 0.065 mmol), andHBTU (27.1 mg, 0.0715 mmol). The reaction mixture was heated to 40° C.,stirred overnight, and then quenched with water. The reaction mixturewas extracted with EtOAc (3×10 mL) and the combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica chromatography (0-50% of a 20%MeOH! DCM in EtOAc) to provide the title compound (0.0128 g, 40% yield).MS (apci) m/z=499.3 (M+H).

The compounds in Table F were prepared and purified according the methodused for the synthesis of Example 53, replacing(R)-2-hydroxy-4-methylpentanoic acid with the appropriate acid startingmaterial.

TABLE F MS (apci) Ex# Structure Chemical Name m/z 54

(S)-4-(6-(4-(2-hydroxy- 3-methylbutanoyl) piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 485.2 (M + H) 55

(R)-4-(6-(4-(3- hydroxybutanoyl) piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 471.2 (M + H) 56

(S)-4-(6-(4-(2- hydroxy-4- methylpentanoyl) piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 499.1 (M + H) 57

(S)-4-(6-(4-(3- hydroxybutanoyl) piperazin-1-yl) pyridin-3-yl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a] pyridine-3- carbonitrile 471.1(M + H) 58

(R)-6-(1-methyl- 1H-pyrazol-4-yl)- 4-(6-(4- (tetrahydrofuran-2-carbonyl)piperazin- 1-yl)pyridin-3-yl) pyrazolo[1,5-a] pyridine-3-carbonitrile 483.1 (M + H) 59

4-(6-(4-(2,2- difluoropropanoyl) piperazin-1-yl) pyridin-3-yl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a] pyridine-3- carbonitrile 477.1(M + H) 60

(S)-6-(1-methyl-1H- pyrazol-4-yl)-4-(6- (4-(tetrahydrofuran-2-carbonyl)piperazin- 1-yl)pyridin-3-yl) pyrazolo[1,5-a] pyridine-3-carbonitrile 483.1 (M + H) 61

(S)-6-(1-methyl-1H- pyrazol-4-yl)-4-(6- (4-(3,3,3-trifluoro-2-hydroxypropanoyl) piperazin-1-yl) pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 511.2 (M + H) 62

6-(1-methyl-1H- pyrazol-4-yl)-4-(6- (4-(2-(tetrahydrofuran-3-yl)acetyl)piperazin- 1-yl)pyridin-3-yl) pyrazolo[1,5-a] pyridine-3-carbonitrile 497.1 (M + H) 63

4-(6-(4-(3-hydroxy- 3-methylpentanoyl) piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 499.1 (M + H)

Example 64

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyrrolidin-1-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(30 mg, 0.078 mmol) and TEA (54 μL, 0.39 mmol) in DMF (3 mL) was added2-chloroacetyl chloride (9.3 μL, 0.117 mmol). The reaction was stirredat ambient temperature for 1 h then pyrrolidine (51.6 μL, 0.62 mmol) wasadded and the reaction was stirred for an additional 2 h. The reactionmixture was quenched with water (15 mL) and extracted with EtOAc (3×20mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, concentrated and purified by silica chromatography (0-50% of20% MeOH/DCM in EtOAc) to provide the title compound (0.0244 g, 63%yield). MS (apci) m/z=496.2 (M+H). ¹H NMR (DMSO) δ 9.20 (d, 1H), 8.61(s, 1H), 8.37 (d, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.82 (dd, 1H), 7.75(d, 1H), 6.97 (d, 1H), 3.85 (s, 3H), 3.60 (m, 8H), 3.37 (s, 2H), 2.53(s, 4H), 1.68 (s, 4H).

Example 65

4-(6-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(40 mg, 0.10 mmol) and pyridine (33.7 μL, 0.42 mmol) in DCM (4 mL) wasadded 3,3-Dimethylbutyryl chloride (0.97 mL, 0.21 mmol). The reactionwas stirred at ambient temperature for 2 h and then quenched with water(10 mL) and extracted with EtOAc (3×15 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, concentrated and purified bysilica chromatography (0-20% MeOH with NH₄OH in DCM) to provide thetitle compound (0.0327 g, 65% yield). MS (apci) m/z=483.2 (M+H).

Example 66

4-(6-(4-isobutyrylpiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.022 mmol) in DCM (2 mL) was added isobutyrylchloride (3.5 mg, 0.033 mmol) and TEA (30 μL, 0.22 mmol). The reactionwas stirred at ambient temperature for 1 h and then purified by reversephase chromatography (0-75% ACN/water) to afford the title compound (9mg, 91% yield). MS (apci) m/z=455.1 (M+H).

Example 67

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-propionylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.022 mmol) in DCM (2 mL) was added propionylchloride (3.0 mg, 0.033 mmol) and TEA (30 μL, 0.22 mmol). The reactionmixture was stirred at ambient temperature for 1 h, then concentrated invacuo and purified by reverse phase chromatography (0-75% ACN/water) toafford the title compound (5 mg, 52% yield). MS (apci) m/z=441.1 (M+H).

The compounds in Table G were prepared and purified according the methodused for the synthesis of Example 67, replacing propionyl chloride withthe appropriate acid halide starting material.

TABLE G MS (apci) Ex# Structure Chemical Name m/z 68

4-(6-(4- (cyclopropanecarbonyl) piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 453.2 (M + H) 69

4-(6-(4- benzoylpiperazin-1- yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyridine-3- carbonitrile 489.1 (M + H)

Example 70

4-(6-(4-butyrylpiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (13 mg, 0.028 mmol) in DCM (2 mL) was added butyrylchloride (4.5 mg, 0.043 mmol) and TEA (40 μL, 0.28 mmol). The reactionmixture was stirred overnight at ambient temperature and then quenchedwith water (5 mL) and extracted with DCM (3×10 mL). The combined organicextracts were concentrated and purified by reverse phase chromatography(0-75% ACN/water) to afford the title compound (9 mg, 65% yield). MS(apci) m/z=455.2 (M+H).

The compounds in Table H were prepared and purified in a similar fashionas described for the synthesis of Example 70, replacing butyryl chloridewith the appropriate acid halide starting material and utilizing theappropriate ACN/water gradient eluent for reverse phase chromatography.

TABLE H MS (apci) Ex# Structure Chemical Name m/z 71

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2-(pyridin-3-yl)acetyl)piperazin-1- yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 504.1 (M + H) 72

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4- picolinoylpiperazin-1-yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3- carbonitrile 490.1 (M + H)73

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4- nicotinoylpiperazin-1-yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3- carbonitrile 490.0 (M + H)74

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4- (tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl) pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 497.1 (M + H)

Example 75

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) in DCM (2 mL) was added3-methylbutanoyl chloride (5.9 mg, 0.049 mmol) and TEA (46 μL, 0.33mmol). The reaction was stirred overnight at ambient temperature andthen quenched with water (5 mL) and extracted with DCM in a PS frit. Thecombined organic extracts were concentrated in vacuo, and the resultingcrude residue was taken up in MeOH (0.3 mL) and sonicated. The resultingsolid was collected by vacuum filtration, washed with Et₂O (3×2 mL) andair dried to afford the title compound (12 mg, 78% yield). MS (apci)m/z=469.2 (M+H).

The compounds in Table I were prepared and purified according the methodused for the synthesis of Example 75, replacing 3-methylbutanoylchloride with the appropriate acid halide starting material.

TABLE I MS (apci) Ex# Structure Chemical Name m/z 76

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(2-(tetrahydro-2H-pyran-4-yl)acetyl)piperazin-1- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 511.2 (M + H) 77

4-(6-(4-(2- cyclopropylacetyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 467.1(M + H) 78

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(2- phenylacetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 503.2 (M + H)

Example 79

4-(6-(4-(3-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(50 mg, 0.130 mmol) in DMF (4.34 mL) were added3-hydroxy-3-methylbutanoic acid (210 □L, 0.195 mmol), DMAP (55.6 mg,0.455 mmol), and EDC-HCl (31.2 mg, 0.163 mmol). After stirring overnightat ambient temperature, the reaction mixture was diluted with water (20mL) and extracted with EtOAc (3×20 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresulting crude residue was purified by silica chromatography (0-50%,20% MeOH/DCM in EtOAc) to provide the title compound (51.1 mg, 80%yield). MS (apci) m/z=485.1 (M+H). ¹H NMR (CDCl₃) δ 8.63 (d, 1H), 8.37(d, 1H), 8.25 (s, 1H), 7.77 (d, 1H), 7.75 (d, 1H), 7.67 (s, 1H), 7.38(s, 1H), 6.78 (d, 1H), 3.98 (s, 3H), 3.80 (m, 2H), 3.75 (m, 2H), 3.63(m, 4H), 2.50 (s, 2H), 1.31 (s, 6H).

The compounds in Table J were prepared and purified according the methodused for the synthesis of Example 79, replacing3-hydroxy-3-methylbutanoic acid with the appropriate acid startingmaterial.

TABLE J MS (apci) Ex# Structure Chemical Name m/z 80

4-(6-(4-((1r,4r)-4- hydroxycyclohexane- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 511.2 (M + H) 81

4-(6-(4-(1- hydroxycyclopropane- 1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6- (1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 469.2 (M + H)

Example 82

(R)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(35 mg, 0.0910 mmol) in DMF (910 μL) was added(R)-2-hydroxy-2-phenylacetic acid (13.9 mg, 0.0.0912 mmol), DMAP (33.4mg, 0.273 mmol), and EDC-HCl (21.8 mg, 0.114 mmol). After stirringovernight at ambient temperature, the reaction mixture was diluted withwater (5 mL) and then extracted with EtOAc (3×5 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by reverse phasechromatography (0-60%, ACN/water) to provide the title compound (32.8mg, 67% yield). MS (apci) m/z=519.1 (M+H). ¹H NMR (CDCl₃) δ 8.61 (d,1H), 8.31 (d, 1H), 8.22 (s, 1H), 7.76 (m, 1H), 7.71 (m, 1H), 7.65 (m,1H), 7.35 (m, 6H), 6.68 (d, 1H), 5.25 (s, 1H), 4.00 (m, 1H), 3.88 (s,3H), 3.80 (m, 1H), 3.62 (m, 2H), 3.37 (m, 3H), 3.00 (s, 1H), 2.86 (m,1H).

Example 82a

(R)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

To a solution of(R)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(19 mg, 0.037 mmol) in DCM (5 mL) was added 5 M HCl in iPrOH (29 μL,0.15 mmol). The mixture was concentrated in vacuo to afford the titlecompound (22 mg, quantitative yield). MS (apci) m/z=519.1 (M+H).

Example 83

(R)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(15 mg, 0.0390 mmol) in DMF (390 μL) was added(R)-2-methoxy-2-phenylacetic acid (9.73 mg, 0.0585 mmol), DMAP (14.3 mg,0.117 mmol), and EDC-HCl (11.6 mg, 0.0605 mmol). After stirringovernight at ambient temperature, the reaction mixture was diluted withMeOH and purified directly using reverse phase chromatography (0-70%ACN/water) to provide the title compound (9.2 mg, 44% yield). MS (apci)m/z=533.2 (M+H).

Example 84

(S)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(15 mg, 0.0390 mmol) in DMF (390 μL) was added(S)-2-methoxy-2-phenylacetic acid (9.73 mg, 0.0585 mmol), DMAP (14.3 mg,0.117 mmol), and EDC-HCl (11.6 mg, 0.0605 mmol). After stirringovernight at ambient temperature, the reaction mixture was diluted withMeOH and then purified directly using reverse phase chromatography(0-70% ACN/water) to provide the title compound (4.0 mg, 19.2% yield).MS (apci) m/z=533.0 (M+H).

Example 85

(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(25 mg, 0.065 mmol) in DMF (2.2 mL) was added(R)-2-hydroxy-3-methylbutanoic acid (11.5 mg, 0.098 mmol), DMAP (28 mg,0.23 mmol), and, finally, EDC-HCl (15.6 mg, 0.081 mmol). After stirringovernight at ambient temperature, the reaction mixture was diluted withwater (15 mL) and then extracted with EtOAc (3×20 mL). The combinedorganic layers was dried over anhydrous Na₂SO₄, filtered, concentratedand purified by silica chromatography (0-50%, 20% MeOH/DCM in EtOAc) toprovide the title compound (7.7 mg, 24.2% yield). MS (apci) m/z=485.2(M+H).

Example 85a

(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

To a solution of(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(17 mg, 0.035 mmol) in DCM (2 mL) was added 5 M HCl in iPrOH (21 μL,0.11 mmol). The mixture was concentrated in vacuo and dried on highvacuum to afford the title compound (18 mg, 98% yield). MS (apci)m/z=485.2 (M+H).

Example 86

(R)-4-(6-(4-(2-methoxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

NaH (1.7 mg, 0.041 mmol) was added to a solution of(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(10 mg, 0.021 mmol) in THF (1 mL) and the reaction mixture was stirredat ambient temperature for 20 min. MeI (41 μL, 0.041 mmol) was added andthe reaction was stirred at ambient temperature for 1 h and thenquenched with water (1 mL). The resulting mixture was extracted with DCM(3×5 mL). The combined organic extracts were concentrated and purifiedby reverse phase chromatography (0-70% ACN/water) to provide the titlecompound (5.5 mg, 53% yield). MS (apci) m/z=499.1 (M+H).

Example 87

4-(6-(4-((cyclopropylmethyl)sulfonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.0219 mmol) in DCM (2 mL) was addedcyclopropylmethanesulfonyl chloride (4.4 mg, 0.028 mmol) followed by TEA(30 μL, 0.22 mmol). The reaction mixture was stirred overnight atambient temperature and then quenched with water (1 mL) and extractedwith DCM (3×5 mL) in a PS frit. The combined DCM extracts wereconcentrated and purified by reverse phase chromatography (0-70%ACN/water) to provide the title compound (10.1 mg, 87% yield). MS (apci)m/z=503.1 (M+H).

The compounds in Table K were prepared according the method used for thesynthesis of Example 87, replacing cyclopropylmethanesulfonyl chloridewith the appropriate sulfonyl chloride starting material, and utilizingthe appropriate ACN/water gradient eluent for reverse phasechromatography purifications.

TABLE K MS (apci) Ex# Structure Chemical Name m/z 88

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4- (methylsulfonyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 463.1 (M + H)89

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4- (neopentylsulfonyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 519.1 (M + H)90

4-(6-(4- (isobutylsulfonyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 505.1(M + H) 91

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((tetrahydro-2H- pyran-4-yl)sulfonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 533.1 (M + H)

Example 92

4-(6-(4-(4-hydroxypiperidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) and DIEA (34 μL, 0.20 mmol) inDriSolv® DCM (164 μL) was added dropwise to a 0° C. solution oftriphosgene (4.9 mg, 0.016 mmol) in DriSolv® DCM (164 μL). Afterstirring the reaction mixture for 1 hour at 0° C., piperidin-4-ol (3.3mg, 0.033 mmol) was added, and the reaction was stirred at ambienttemperature overnight. The reaction mixture was diluted with EtOAc (0.5mL), vacuum filtered, and the solids were rinsed with EtOAc (3×0.5 mL)to provide the title compound as a white solid (16 mg, 93% yield). MS(apci) m/z=512.2 (M+H).

Example 93

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(piperidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) and DIEA (34 μL, 0.20 mmol) inDriSolv® DCM (328 μL+100 μL rinse) was added dropwise to a 0° C.solution of triphosgene (4.9 mg, 0.016 mmol) in DriSolv® DCM (328 μL).After stirring for 1 hour at 0° C., piperidine (4.9 μL, 0.049 mmol) wasadded and the reaction mixture was stirred at ambient temperature for 3h. The reaction mixture was directly purified by reverse phasechromatography (5-80% ACN/water) to yield a solid that contained mostlydesired product, which was triturated with MTBE (2 mL) to provide thetitle compound (7.0 mg, 43% yield). MS (apci) m/z=496.1 (M+H).

Example 94

4-(6-(4-(3,3-difluoropiperidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) and DIEA (34 μL, 0.20 mmol) inDriSolv® DCM (428 μL) was added dropwise to a 0° C. solution oftriphosgene (4.9 mg, 0.016 mmol) in DriSolv® DCM (328 μL). After themixture was stirred for 1 h at 0° C., 3,3-difluoropiperidinehydrochloride (7.8 mg, 0.049 mmol) was added and the reaction mixturewas stirred at ambient temperature for 3 h. The reaction mixture wasthen directly purified by reverse phase chromatography (5-80% ACN/water)to yield a solid that contained mostly desired product, which wastriturated with MTBE (2 mL) to provide the title compound (2.2 mg, 13%yield). MS (apci) m/z=532.1 (M+H). ¹⁹F NMR (CDCl₃) δ −102.6.

Example 95

4-(6-(4-(7-azabicyclo[2.2.1]heptane-7-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) and DIEA (46 μL, 0.26 mmol) inDriSolv® DCM (164 μL) was added dropwise to a 0° C. solution oftriphosgene (4.9 mg, 0.016 mmol) in DriSolv® DCM (164 μL) and stirredfor 4 h, followed by addition of 7-azabicyclo[2.2.1]heptanehydrochloride (4.4 mg, 0.033 mmol) in one portion. The reaction mixturewas warmed to ambient temperature and stirred for 3 h. Additional7-azabicyclo[2.2.1]heptane hydrochloride (4.4 mg, 0.033 mmol) was addedand the reaction mixture was stirred for an additional 2 h to reachcompletion as shown by LCMS. The reaction mixture was then dissolved inminimal amount of warm DMSO and directly purified by reverse-phasechromatography (C18, 5-60% ACN/water) to provide the title compound (4.5mg, 26% yield). MS (apci) m/z=508.1 (M+H).

Example 96

(R)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(1-hydroxybutan-2-yl)piperazine-1-carboxamide

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(25 mg, 0.0650 mmol) and DIEA (68.0 μL, 0.390 mmol) in DriSolv® DCM (325μL) was added dropwise to a 0° C. solution of triphosgene (9.65 mg,0.0325 mmol) in DriSolv® DCM (325 μL). After stirring this reactionmixture for 1.5 h at 0° C., (R)-2-aminobutan-1-ol (6.96 mg, 0.0780 mmol)was added and the reaction was stirred at ambient temperature overnight.The reaction mixture was then diluted with DMSO (0.5 mL), warmed (tosolubilize particulate matter), concentrated in vacuo to ½ the originalvolume and purified by reverse phase chromatography (5-50% ACN/water) toprovide the title compound (11.3 mg, 34% yield). MS (apci) m/z=500.1(M+H).

Example 97

(S)-4-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) and DIEA (34 μL, 0.20) mmol) inDriSolv® DCM (164 μL) was added dropwise to a 0° C. solution oftriphosgene (4.9 mg, 0.016 mmol) in DriSolv® DCM (164 μL). Afterstirring for 30 min at 0° C., (S)-3-methoxypyrrolidine hydrochloride(4.5 mg, 0.033 mmol) was added and the reaction mixture was stirred atambient temperature for 48 h. The reaction mixture was then directlypurified by reverse-phase chromatography (C18, 5-50% ACN/water) toprovide the title compound as a white solid (11.7 mg, 68% yield). MS(apci) m/z=512.2 (M+H). ¹H NMR (CDCl₃) δ 8.61 (d, 1H), 8.36 (d, 1H),8.24 (s, 1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.66 (s, 1H), 7.37 (d, 1H),6.77 (d, 1H), 3.97 (s, 3H), 3.95 (m, 1H), 3.37-3.72 (m, 12H), 3.33 (s,3H), 1.98-2.04 (m, 1H), 1.88-1.94 (m, 1H).

The compounds in Table L were prepared in a similar fashion as describedfor the syntheses of Examples 96 and 97, replacing (R)-2-aminobutan-1-olor (S)-3-methoxypyrrolidine hydrochloride with the appropriate aminestarting material.

TABLE L MS (apci) Ex # Structure Chemical Name m/z 98

4-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)- N,N-diethylpiperazine-1- carboxamide 484.1(M + H) 99

(R)-4-(6-(4-(3-hydroxy- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 498.2 (M + H) 100

(S)-4-(6-(4-(3-hydroxy- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 498.2 (M + H) 101

4-(6-(4-(3,3-difluoro- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 518.1 (M + H) 102

(S)-4-(6-(4-(3-fluoro- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 500.1 (M + H) 103

(R)-4-(6-(4-(3-fluoro- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 500.1 (M + H) 104

(R)-4-(6-(4-(3-methoxy- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 512.1 (M + H) 105

(S)-4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N- (tetrahydrofuran-3-yl)-piperazine-1-carboxamide 498.1 (M + H) 106

(R)-4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N- (tetrahydrofuran-3-yl)-piperazine-1-carboxamide 498.2 (M + H) 107

(R)-4-(6-(4-(3-isopropoxy- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 540.2 (M + H) 108

(S)-4-(6-(4-(3-isopropoxy- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 540.2 (M + H) 109

4-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- methyl-N-phenylpiperazine-1- carboxamide518.2 (M + H) 110

(R)-4-(6-(4-(2-(methoxy- methyl)pyrrolidine-1- carbonyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridine-3-carbonitrile 526.2 (M + H) 111

(S)-4-(6-(4-(2-(methoxy- methyl)pyrrolidine-1- carbonyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridine-3-carbonitrile 526.2 (M + H) 112

(S)-4-(6-(4-(2-cyano- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 507.1 (M + H) 113

(S)-6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2-(trifluoro-methyl)pyrrolidine-1- carbonyl)piperazin-1-yl)-pyridin-3-yl)pyrazolo[1,5-a]- pyridine-3-carbonitrile 550.1 (M + H) 114

4-(6-(4-(4-fluoropiperidine-1- carbonyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridine-3-carbonitrile 514.1 (M + H) 115

4-(6-(4-(4,4-difluoropiperidine- 1-carbonyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridine-3-carbonitrile 532.2 (M + H) 116

4-(6-(4-(3-fluoropiperidine-1- carbonyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridine-3-carbonitrile 514.1 (M + H) 117

4-(6-(4-(5-azaspiro[2.4]- heptane-5-carbonyl)piperazin-1-yl)-pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine-3- carbonitrile 508.1 (M + H) 118

4-(6-(4-(3,3-dimethyl- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 510.2 (M + H) 119

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(morpholine-4-carbonyl)piperazin-1-yl)- pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 498.1 (M + H) 120

6-(1-methyl-1H-pyrazol-4-yl)- 4-(6-(4-(4-methylpiperazine-1-carbonyl)piperazin-1-yl)- pyridin-3-yl)pyrazolo[1,5-a]-pyridine-3-carbonitrile 511.2 (M + H) 121

4-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (tetrahydro-2H-pyran-4-yl)-piperazine-1-carboxamide 512.2 (M + H) 122

(S)-4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)- N-(1-hydroxybutan-2-yl)-piperazine-1-carboxamide 500.1 (M + H) 123

4-(6-(4-(hexahydro-1H-furo- [3,4-c]pyrrole-5-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine-3- carbonitrile 524.2 (M + H) 124

4-(6-(4-(2,2-dimethyl- pyrrolidine-1-carbonyl)-piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 510.1 (M + H)

Example 125

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(100 mg, 0.260 mmol) and DIEA (136 μL, 0.780 mmol) in DCM (1.30 mL) atambient temperature was treated with pyrrolidine-1-carbonyl chloride (52mg, 0.39 mmol). The suspension was stirred overnight at ambienttemperature and concentrated in vacuo to remove the bulk of the DCM andthen diluted with hot DMSO (1 mL). The resulting solution was directlypurified by reverse phase chromatography (5-60% ACN/water) to providethe title compound (66.4 mg, 53% yield). MS (apci) m/z=482.1 (M+H). ¹HNMR (CDCl₃) δ 8.61 (d, 1H), 8.35 (d, 1H), 8.24 (s, 1H), 7.77 (s, 1H),7.74 (dd, 1H), 7.66 (s, 1H), 7.37 (d, 1H), 6.76 (d, 1H), 3.97 (s, 3H),3.65-3.68 (m, 4H), 3.38-3.44 (m, 8H), 1.82-1.86 (m, 4H).

Example 125a

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 125, 50 mg, 0.10 mmol) in DCM (5 mL) was added 5 M HCl in iPrOH(29 μL, 0.15 mmol). After 30 min, the mixture was concentrated in vacuoto afford the title compound as a white solid (55 mg, quantitativeyield). MS (apci) m/z=482.0 (M+H).

Example 126

4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperazine-1-carboxamide

To a mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(15 mg, 0.039 mmol) and DIEA (34 μL, 0.20 mmol) in DCM (195 μL) wasadded 2-isocyanatopropane (3.3 mg, 0.039 mmol) in one portion at ambienttemperature. The resulting mixture was stirred overnight and thendiluted with EtOAc (0.5 mL). The resulting suspension was vacuumfiltered and successively rinsed with EtOAc (2 mL) and MTBE (1 mL). Theisolated solids were taken up in DMSO and purified by reverse phasechromatography (5-60% ACN/water) to afford the title compound (7.9 mg,43% yield). MS (apci) m/z=470.2. ¹H NMR (CDCl₃) δ 8.62 (d, 1H), 8.36 (d,1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.74 (dd, 1H), 7.66 (s, 1H), 7.37 (d,1H), 6.75 (d, 1H), 4.21 (d, 1H), 4.00 (m, 1H), 3.97 (s, 3H), 3.68-3.71(m, 4H), 3.50-3.53 (m, 4H), 1.18 (m, 6H).

Example 127

4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpiperazine-1-carboxamide

To a suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (16 mg, 0.035 mmol) and DIEA (30 μL, 0.17 mmol) in DCM(175 μL) was added isocyanatobenzene (4.6 mg, 0.038 mmol). The resultingmixture was stirred at ambient temperature for 4 h and then diluted withEtOAc (0.5 mL), vacuum filtered and rinsed with EtOAc (2 mL) to affordthe title compound (18 mg, 100% yield). MS (apci) m/z=504.1 (M+H).

The compounds in Table M were prepared according the method used for thesynthesis of Example 127, replacing isocyanatobenzene with theappropriate isocyanate starting material.

TABLE M MS (apci) Ex # Structure Chemical Name m/z 128

N-(tert-butyl)-4-(5-(3- cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperazine-1- carboxamide 484.1 (M + H) 129

N-benzyl-4-(5-(3-cyano-6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin- 4-yl)pyridin-2-yl)- piperazine-1-carboxamide518.1 (M + H)

Example 130

4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxyethyl)-N-methylpiperazine-1-carboxamide2,2,2-trifluoroacetate

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (30 mg 0.066 mmol) in DMF (1.0 mL) was added(4-nitrophenyl) carbonochloridate (18.88 mg, 0.094 mmol), DMAP (1.91 mg,0.016 mmol) and DIEA (83 □L, 0.47 mmol). The mixture was stirred atambient temperature for 12 h, and then 2-methoxy-N-methyl-ethanamine(7.65 mg, 0.086 mmol) was added in one portion. The reaction mixture wasstirred at 45° C. for 12 h and then directly purified by reverse-phasepreparative HPLC (10 to 80% acetonitrile/water with 0.1 v/v % TFA) togive the title compound (10 mg, 25% yield). MS (ES-API Pos) m/z=500.4(M+H), 522.3 (M+Na).

The compounds in Table N were prepared according the method describedfor the synthesis of Example 130, replacing2-methoxy-N-methyl-ethanamine with the appropriate amine startingmaterial. All compounds were purified similarly by reverse-phasepreparative HPLC (10 to 80% acetonitrile/water with 0.1 v/v % TFA or0.04 v/v % NH₄OH) to yield the title compound as TFA salt unlessotherwise stated.

TABLE N MS (apci) Ex # Structure Chemical Name m/z 131

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-N-cyclopropyl-piperazine-1-carboxamide 2,2,2-trifluoroacetate 468.2 (M + H) 132

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-N,N-dimethyl-piperazine-1-carboxamide 456.2 (M + H) 133

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-N-isobutylpiperazine- 1-carboxamide484.2 (M + H) 134

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-N-ethylpiperazine-1- carboxamide456.2 (M + H) 135

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-N-(2-methoxyethyl)-piperazine-1-carboxamide 486.2 (M + H) 136

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-N-ethyl-N-methyl-piperazine-1-carboxamide 470.2 (M + H)

Example 137

N-(tert-butyl)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-sulfonamide

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.022 mmol) in DCM (2 mL) was addedtert-butylsulfamoyl chloride (4.5 mg, 0.026 mmol) followed by TEA (30μL, 0.22 mmol). The mixture was stirred overnight at ambient temperatureand then quenched with water and extracted with DCM in a PS frit. Thecombined DCM extracts were concentrated and purified by reverse phasechromatography (0-80% ACN/water) to provide the title compound (2.6 mg,23% yield). MS (apci) m/z=520.2 (M+H).

Example 138

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrrolidin-1-ylsulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) in DCM (2 mL) was addedpyrrolidine-1-sulfonyl chloride (5.6 mg, 0.033 mmol) followed by TEA (46μL, 0.33 mmol). The mixture was stirred overnight at ambient temperatureand then quenched with water and extracted with DCM in a PS frit. Thecombined DCM extracts were concentrated and purified by reverse phasechromatography (0-80% ACN/water) to provide the title compound (13 mg,77% yield). MS (apci) m/z=518.1 (M+H).

Example 139

4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.0328 mmol) in DMF (0.2 mL) and TEA (22.9 μL,0.164 mmol) was treated with (bromomethyl)benzene (11.2 mg, 0.0656mmol). The reaction mixture was stirred at ambient temperature for 1 hand then directly purified by reverse phase chromatography (0-70%ACN/water) to afford the title compound (12.3 mg, 79% yield). MS (apci)m/z=475.1 (M+H).

Example 140

4-(6-(4-(4-chlorophenethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (20 mg, 0.044 mmol), 1-(2-bromoethyl)-4-chlorobenzene(12 mg, 0.052 mmol) and N-ethyl-N-isopropylpropan-2-amine (39 μL, 0.22mmol) in DMA (219 μL) was heated at 65° C. overnight, then at 100° C.for additional 2 d to reach completion as indicated by LCMS. Thereaction mixture was directly purified by reverse phase chromatography(0-75% ACN/water) to yield the title compound (4.5 mg, 19% yield). MS(apci) m/z=523.0 (M+H).

Example 141

4-(6-(4-formylpiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was isolated as a side product from thechromatographic purification process in Example 140 as a white solid(1.8 mg, 9.7% yield). MS (apci) m/z=413.1 (M+H).

Example 142

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(1-methyl-2-oxopyrrolidin-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(25 mg, 0.065 mmol) and 3-bromo-1-methylpyrrolidin-2-one (23 mg, 0.13mmol) in DMF (1.3 mL) was added Cs₂CO₃ (42 mg, 0.13 mmol). The reactionmixture was heated to 80° C. and stirred overnight. After cooling toambient temperature and diluting with water (10 mL), the reaction pH wasadjusted to 8 with 1 M HCl_((aq)) and subsequently extracted with EtOAc(3×15 mL). The combined organic extracts were washed with brine (15 mL),dried (Na₂SO₄), filtered, concentrated and purified by silicachromatography (0-10% MeOH/DCM) to afford the title compound (2.8 mg,8.8% yield). MS (apci) m/z=482.1 (M+H).

Example 143

2-(4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide2,2,2-trifluoroacetate

To a mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (30 mg, 0.066 mmol) in ACN (1 mL) as ambient temperaturewere added K₂CO₃ (18 mg, 0.13 mmol) and 2-chloro-N,N-dimethylacetamide(9.6 mg, 0.079 mmol). The reaction mixture was stirred at ambienttemperature for 12 h and purified by reverse-phase preparative HPLC (10to 80% acetonitrile/water with 0.1 v/v % TFA) to give the title compound(23 mg, 60% yield). MS (ES-API Pos) m/z=470.3 (M+H).

The compounds in Table O were prepared according the method describedfor the synthesis of Example 143, replacing2-chloro-N,N-dimethylacetamide with the appropriate alkyl halide. Allcompounds were purified similarly by reverse-phase preparative HPLC (10to 80% acetonitrile/water with 0.1 v/v % TFA or 0.04 v/v % NH₄OH) toyield the title compound as TFA salt unless otherwise stated.

TABLE O MS (apci) Ex # Structure Chemical Name m/z 144

2-(4-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)piperazin-1-yl)-N-isopropylacetamide 2,2,2-trifluoroacetate 484.2 (M + H) 145

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(2-oxo-2- (pyrrolidin-1-yl)ethyl)-piperazin-1-yl)pyridin-3-yl)- pyrazolo[1,5-a]pyridine-3- carbonitrile2,2,2-trifluoro- acetate 496.2 (M + H) 146

3-(4-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)piperazin-1-yl)-N,N-dimethylpropan- amide 2,2,2-trifluoroacetate 484.2 (M + H)

Example 147

4-(6-(4-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(25 mg, 0.0650 mmol) and (2R,3R)-2-methyl-3-phenyloxirane (8.73 mg,0.0650 mmol) in methanol (325 μL) was stirred in a sealed vial andheated at 75° C. for 40 h. After cooling to ambient temperature, thereaction mixture was directly purified by reverse phase chromatography(C18, 5-50% ACN/water) to afford the title compound (17.0 mg, 50%yield). MS (apci) m/z=519.2 (M+H).

The compounds in Table P were prepared by a similar fashion as describefor the synthesis of Example 147, replacing(2R,3R)-2-methyl-3-phenyloxirane with the appropriate oxirane startingmaterial.

TABLE P MS (apci) Ex # Structure Chemical Name m/z 148

4-(6-(4-(2-hydroxy-3,3- dimethylbutyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine-3- carbonitrile 485.1 (M + H) 149

4-(6-(4-((1S,2S)-1-hydroxy- 1-phenylpropan-2-yl)-piperazin-1-yl)pyridin-3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]- pyridine-3-carbonitrile 519.2 (M + H) 150

(S)-4-(6-(4-(2-hydroxy- butyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo- [1,5-a]pyridine-3-carbonitrile 457.2 (M + H) 151

(R)-4-(6-(4-(2-hydroxy-3- methoxypropyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 473.1 (M + H) 152

4-(6-(4-(2-(4-chlorophenyl)- 2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine- 3-carbonitrile 539.1 (M + H) 153

(R)-4-(6-(4-(2-(3-chloro- phenyl)-2-hydroxyethyl)-piperazin-1-yl)pyridin-3- yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]- pyridine-3-carbonitrile 539.1 (M + H) 154

4-(6-(4-(2-(2,6-difluoro- phenyl)-2-hydroxyethyl)-piperazin-1-yl)pyridin-3- yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 541.1 (M + H)

Example 155

4-(6-(4-((1r,2r)-2-hydroxycyclohexyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(25 mg, 0.065 mmol) and 7-oxabicyclo[4.1.0]heptane (6.4 mg, 0.065 mmol)in methanol (325 μL) was stirred in a sealed vial at 75° C. for 40 h.After cooling to ambient temperature, the reaction mixture was dilutedwith cold MeOH (325 μL), vacuum filtered, and rinsed sequentially withcold MeOH and Et₂O (1 mL each) to afford the title compound (19.9 mg,62% yield). MS (apci) m/z=483.2 (M+H).

The compounds in Table Q were prepared according the method used for thesynthesis of Example 155, replacing 7-oxabicyclo[4.1.0]heptane with theappropriate oxirane starting material. All compounds were purifiedsimilarly to the method described therein, utilizing either cold MeOHalone as the solvent for rinsing the solid product or cold MeOH andEt₂O.

TABLE Q MS (apci) Ex # Structure Chemical Name m/z 156

4-(6-(4-(2-hydroxy-2- methylpropyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridine-3-carbonitrile 457.2 (M + H) 157

(S)-4-(6-(4-(2-hydroxy- propyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridine-3-carbonitrile 443.1 (M + H) 158

(R)-4-(6-(4-(2-hydroxy- propyl)piperazin-1-yl)-pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridine-3-carbonitrile 443.1 (M + H) 159

4-(6-(4-((3r,4s)-4-hydroxy- tetrahydrofuran-3-yl)-piperazin-1-yl)pyridin-3- yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 471.1 (M + H) 160

4-(6-(4-(2-hydroxy-3- methylbutyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridine-3-carbonitrile 471.2 (M + H) 161

(R)-4-(6-(4-(2-hydroxy-2- phenylethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridine-3-carbonitrile 505.1 (M + H) 162

(S)-4-(6-(4-(2-hydroxy-2- phenylethyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 505.1 (M + H) 163

4-(6-(4-((1r,2r)-2-hydroxy- cyclopentyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)- pyrazolo[1,5-a]pyridine-3-carbonitrile 469.1 (M + H) 164

4-(6-(4-(2-(4-fluorophenyl)- 2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridine-3-carbonitrile 523.1 (M + H) 165

rac-4-(6-(4-((2R*,3S*)-3- hydroxybutan-2-yl)- piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 457.1 (M + H)

Example 166

tert-butyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

A solution of tert-butyl7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate(Intermediate R2; 91 mg, 0.219 mmol) in dioxane (1.5 mL) was added to3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 62.6 mg, 0.169 mmol). Theresulting mixture was treated with 2 M Na₂CO_(3(aq)) (421 μL, 0.843mmol) and Pd(PPh₃)₄ (9.74 mg, 0.00843 mmol). The resulting reactionmixture was purged with nitrogen, then sealed and stirred at 90° C.overnight. After cooling to ambient temperature, the reaction mixturewas partitioned between H₂O (10 mL) and DCM (10 mL). Afterphase-separation and extracting the aqueous layer with DCM (2×10 mL),the organic layers were combined and concentrated and the residue waspurified by silica chromatography (0-100% EtOAc/hexanes followed by0-10% MeOH/EtOAc) to afford the title compound contaminated with Ph₃PO,which was removed by trituration with MTBE to yield the title product(19.4 mg, 23% yield). MS (apci) m/z=511.2 (M+H).

Example 167

4-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of tert-butyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate(18.7 mg, 0.0366 mmol) in EtOH (0.2 mL) was added 5 M HCl in iPrOH (293μL, 1.46 mmol). The resulting suspension was stirred at ambienttemperature overnight and then filtered. The isolated solids were rinsedwith Et₂O (3 mL) and then dried in vacuo to afford the title compound(15.5 mg, 88% yield). MS (apci) m/z=411.1 (M+H).

Example 168

4-(6-(4-(3-hydroxy-3-methylbutanoyl)-4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

DIEA (22 μL, 0.12 mmol), 3-hydroxy-3-methylbutanoic acid (4.9 mg, 0.041mmol), and HATU (12 mg, 0.031 mmol) were added sequentially to asolution of4-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.021 mmol) in ACN (0.4 mL). The reactionmixture was stirred for 2 d at ambient temperature and then directlypurified by reverse phase chromatography (5-75% ACN/water) to afford thetitle compound (10.8 mg, 98% yield). MS (apci) m/z=511.1 (M+H).

Example 169

4-(6-(4-(3,3-dimethylbutanoyl)-4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.0103 mmol) in DCM (0.4 mL) was added DIEA (10.8μL, 0.0621 mmol) and 3,3-dimethylbutanoyl chloride (2.17 μL, 0.0155mmol) and the reaction mixture was stirred at ambient temperature 2 d.The resulting suspension was vacuum filtered and the filter cake wasrinsed successively with water (1 mL) and Et₂O (2×1 mL), then dried invacuo to afford the title compound (3.2 mg, 61% yield). MS (apci)m/z=509.2 (M+H).

Example 170

(1S,4S)-tert-butyl5-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

(1S,4S)-tert-butyl5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(Intermediate R3; 48 mg, 0.12 mmol), 2 M Na₂CO_(3(aq)) (236 μL, 0.47mmol), and Pd(PPh₃)₄ (5.5 mg, 0.0047 mmol) were added sequentially to asolution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 35 mg, 0.0943 mmol) indioxane (0.4 mL). The resulting reaction mixture was purged withnitrogen, then sealed and stirred at 90° C. overnight. The reactionmixture was cooled to ambient temperature and then diluted with H₂O (5mL). After vigorous stirring the resulting suspension was extracted withDCM (2×15 mL). The combined organic extracts were concentrated andpurified by silica chromatography (25-100% EtOAc/hexanes then 0-10%MeOH/EtOAc) to afford the title compound (12.1 mg, 26% yield). MS (apci)m/z=497.1 (M+H).

Example 171

4-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of (1S,4S)-tert-butyl5-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(11 mg, 0.022 mmol) in EtOH (0.2 mL) was added 5 M HCl in iPrOH (301 μL,1.5 mmol). The resulting suspension was stirred at ambient temperaturefor 4 h. LCMS indicated continued presence of starting material.Additional 5 M HCl in iPrOH (0.2 mL) was added. The reaction was stirredovernight and then filtered. The filter cake was rinsed with Et₂O (3 mL)and dried in vacuo to afford the title compound (7.6 mg, 73% yield). MS(apci) m/z=397.1 (M+H).

Example 172

4-(6-((1S,4S)-5-(3,3-dimethylbutanoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

DIEA (13.4 μL, 0.0767 mmol) and 3,3-dimethylbutanoyl chloride (2.7 μL,0.019 mmol) were added sequentially to a suspension of4-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (6 mg, 0.0128 mmol) in DCM (0.4 mL). The resultingsolution was stirred overnight at ambient temperature and then quenchedwith MeOH (0.1 mL). The solution was partially concentrated in vacuo andthen purified directly by silica chromatography (0-10% MeOH/EtOAc) toafford the title compound (5.0 mg, 79% yield). MS (apci) m/z=495.2(M+H).

Example 173

tert-butyl3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate, (Intermediate P5; 41.3 mg, 0.111 mmol) indioxane (1 mL) was added tert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(Intermediate R4; 60 mg, 0.144 mmol). The resulting mixture was treatedwith 2 M Na₂CO_(3(aq)) (278 μL, 0.56 mmol), and Pd(PPh₃)₄ (6.42 mg,0.0056 mmol) and then sparged with nitrogen, sealed and heated at 90° C.overnight. The reaction mixture was cooled to ambient temperature andthen diluted with H₂O (10 mL) and filtered. The isolated solids weredissolved in MTBE. The aqueous phase was washed with DCM (10 mL) and thecombined organic extracts were concentrated in vacuo. The resultingresidue was purified by silica chromatography (25-100% EtOAc/hexanes) toafford the title compound contaminated with Ph₃PO, which was removed viatrituration with MTBE (3 mL) to yield the title compound (15.8 mg, 28%yield). MS (apci) m/z=511.1 (M+H).

Example 174

4-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of tert-butyl3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(14.7 mg, 0.0288 mmol) in EtOH (0.2 mL) was added 5 M HCl in iPrOH (305μL, 1.53 mmol). After stirring the suspension at ambient temperature for2 h, additional 5 M HCl in iPrOH (0.3 mL, 1.50 mmol) was added andstirring continued overnight. The solids were collected by filtration,rinsed with Et₂O (3 mL) and then dried in vacuo to afford the titlecompound (10 mg, 72% yield). MS (apci) m/z=411.1 (M+H).

Example 175

4-(6-(8-(3,3-dimethylbutanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (4.5 mg, 0.00931 mmol) in DCM (0.4 mL) was added DIEA(9.7 μL, 0.056 mmol) and 3,3-dimethylbutanoyl chloride (2.0 μL, 0.014mmol). The reaction mixture was stirred at ambient temperatureovernight. The resulting suspension was vacuum filtered and the filtercake was rinsed with Et₂O (3×1 mL) and then dried in vacuo to afford thetitle compound (4.7 mg, 99% yield). MS (apci) m/z=509.2 (M+H).

Example 176

tert-butyl(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate

In a pressure tube a solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 53.7 mg, 0.145 mmol),tert-butyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin-4-yl)carbamate(Intermediate R8; 70 mg, 0.174 mmol) and Pd(PPh₃)₄ (8.4 mg, 0.0072 mmol)in dioxane (1.2 mL) was treated with 2 M Na₂CO_(3(aq)) (362 μL, 0.72mmol). The resulting reaction mixture was purged with nitrogen, sealedand then heated at 90° C. overnight. The reaction mixture was cooled toambient temperature and diluted with water (3 mL). The resultingsuspension was vacuum filtered, and the solids were rinsed withadditional water to afford the title compound (57.9 mg, 83% yield). MS(apci) m/z=499.1 (M+H).

Example 177

4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of to tert-butyl(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate(56 mg, 0.112 mmol) in EtOH (0.2 mL) was added 5 M HCl in iPrOH (449 μL,2.25 mmol). After stirring at ambient temperature 3 d the resultingsuspension was vacuum filtered, and the solids were rinsed with Et₂O (3mL) and then dried in vacuo to afford the title compound (44.7 mg, 84%yield). MS (apci) m/z=399.1 (M+H).

Example 178

(R)—N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)tetrahydrofuran-2-carboxamide

4-(6-(4-Aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.0212 mmol) was treated sequentially with asolution of (R)-tetrahydrofuran-2-carboxylic acid (4.9 mg, 0.042 mmol)in DMA (0.4 mL), DIEA (22 μL, 0.13 mmol) and HATU (12.1 mg, 0.032 mmol).The resulting reaction mixture was stirred overnight at ambienttemperature and then directly purified by chromatography (5-75%ACN/water) to afford the title compound (10.6 mg, quantitative yield).MS (apci) m/z=497.0 (M+H).

The compounds in Table R were prepared according the method used for thesynthesis of Example 178, replacing (R)-tetrahydrofuran-2-carboxylicacid with the appropriate acid starting material and using either DMA(or DMF) as solvent.

TABLE R MS (apci) Ex # Structure Chemical Name m/z 179

N-(1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4-yl)- pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin- 4-yl)-2-hydroxy-2- methylpropanamide 485.1(M + H) 180

(S)-N-(1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)piperidin-4-yl)-2-hydroxypropan- amide 471.1 (M + H) 181

(R)-N-(1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)piperidin-4-yl)-2-hydroxypropan- amide 471.0 (M + H) 182

(S)-N-(1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)piperidin-4-yl)tetrahydrofuran-2- carboxamide 497.1 (M + H)

Example 183

N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-2-methoxyacetamide

A solution of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.021 mmol) in DMA (0.4 mL) was treated withDIEA (15 μL, 0.085 mmol) and 2-methoxyacetyl chloride (3.5 mg, 0.032mmol). The resulting clear solution was stirred overnight at ambienttemperature. LCMS indicated no reaction progress and acid halidedegradation to acid was suspected. The reaction mixture was thereforetreated with HATU (20 mg, 0.0526 mmol). After stirring the reactionmixture for an additional 2 h at ambient temperature, LCMS indicatedcomplete consumption of the carbonitrile starting material. The reactionmixture was directly purified by chromatography (5-75% ACN/water) toafford the title compound (8.5 mg, 85% yield). MS (apci) m/z=471.1(M+H).

Example 184

N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)benzamide

A solution of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (8 mg, 0.017 mmol) in DCM (0.3 mL) was treated with DIEA(11.82 μL, 0.068 mmol) and benzoyl chloride (3.9 μL, 0.034 mmol). Theresulting clear solution was stirred 2 d at ambient temperature. Thereaction mixture was vacuum filtered, and the solids were rinse withEt₂O (3×1 mL) and dried in vacuo to afford the title compound (4.8 mg,56% yield). MS (apci) m/z=503.1 (M+H).

Example 185

N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)isobutyramide

A solution of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (40 mg, 0.085 mmol) in DMA (0.5 mL) was treated withDIEA (59 μL, 0.34 mmol) and isobutyryl chloride (13.4 μL, 0.13 mmol).The resulting clear solution was stirred overnight at ambienttemperature. The reaction mixture was directly purified bychromatography (5-80%, ACN/water) to afford the title compound (26.4 mg,66% yield). MS (apci) m/z=469.2 (M+H).

Example 185a

N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)isobutyramidehydrochloride

A solution ofN-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)isobutyramide(26.4 mg, 0.056 mmol) in a 4:1 solvent mixture of DCM/MeOH (3 mL) wastreated with 5 M HCl in iPrOH (113 μL, 0.56 mmol). The resulting clearsolution was stirred 10 min at ambient temperature and then concentratedin vacuo. The residue was diluted with Et₂O (5 mL) and concentrated invacuo to afford the title compound (30.3 mg, quantitative yield). MS(apci) m/z=469.2 (M+H).

Example 186

3-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-1,1-dimethylurea

To a suspension of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.02121 mmol) in DCM (0.2 mL) and DIEA (18 μL,0.11 mmol) at ambient temperature was added dimethylcarbamic chloride(4.9 μL, 0.053 mmol). The suspension was stirred overnight at ambienttemperature before treated with additional DIEA (20 □L, 0.1148 mmol) anddimethylcarbamic chloride (10 □L, 0.1090 mmol). The reaction mixture wasstirred at ambient temperature for another 4 d, then diluted with ACNand directly purified by reverse phase chromatography (5-75% ACN/water)to provide the title compound (6.4 mg, 64% yield). MS (apci) m/z=470.2(M+H).

Example 187

1-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-3-isopropylurea

To a suspension of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.021 mmol) in DCM (0.2 mL) and DIEA (18 μL,0.11 mmol) was added 2-isocyanatopropane (2.7 mg, 0.032 mmol). Thesuspension was stirred at ambient temperature overnight and then vacuumfiltered. The isolated solids were rinsed with Et₂O and dried in vacuoto afford the title compound (7.3 mg, 71% yield). MS (apci) m/z=484.2(M+H).

Example 188

Isopropyl(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate

To a suspension of4-(6-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.021 mmol) in DCM (0.2 mL) and DIEA (18 μL,0.11 mmol) was added isopropyl carbonochloridate (3.9 mg, 0.032 mmol).The suspension was stirred at ambient temperature overnight and thenvacuum filtered. The isolated solids were rinsed with Et₂O and dried invacuo to afford the title compound (5.7 mg, 55% yield). MS (apci)m/z=485.2 (M+H).

Example 189

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 13.6 mg, 0.043 mmol) and1-(piperidin-4-yl)pyrrolidin-2-one (21.6 mg, 0.13 mmol) in DMSO (0.3 mL)were combined in a microwave vessel. The resulting thick suspension wassubjected to microwave irradiation at 125° C. for 1 h. The reactionmixture was directly purified by reverse phase chromatography (5-90%ACN/water). The chromatographic fractions containing the title compoundwere combined, concentrated in vacuo and then triturated with MTBE toprovide the title compound (6.3 mg, 32% yield). MS (apci) m/z=467.1(M+H).

Example 190

(S)-4-(6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.047 mmol) and(S)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one (26.0 mg, 0.14 mmol)was added DMSO (0.3 mL) were combined in a microwave vessel. Theresulting thick suspension was subjected to microwave irradiation at125° C. for 1 h. The reaction mixture was directly purified by reversephase chromatography (5-75% ACN/water) to afford the title compound(12.4 mg, 55% yield). MS (apci) m/z=483.0 (M+H).

Example 191

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-oxooxazolidin-3-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 3-(piperidin-4-yl)oxazolidin-2-one hydrochloride (29 mg,0.14 mmol) in MeOH (0.5 mL) was filtered through a basic resin(Stratospheres MP-HCO3, 100 mg, 0.18 mmol/g) and concentrated in vacuo.The resulting residue was taken up in DMSO (0.3 mL) and added to amicrowave vessel containing4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.047 mmol). The resulting thick suspension wassubjected to microwave irradiation at 125° C. for 1 h. The reactionmixture was directly purified by reverse phase chromatography (5-75%ACN/water) to afford the title compound (9.7 mg, 44% yield). MS (apci)m/z=469.1 (M+H).

Example 192

tert-butyl((1R,3s,5S)-8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate

In a pressure tube a solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 45.4 mg, 0.12 mmol),tert-butyl ((1R,3s,5S)-8-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate(Intermediate R5; 63 mg, 0.15 mmol) and Pd(PPh₃)₄ (7.1 mg, 0.0061 mmol)in dioxane (1.2 mL) was treated with 2 M Na₂CO_(3(aq)) (306 μL, 0.61mmol). The resulting reaction mixture was sparged with nitrogen, sealedand heated at 90° C. overnight. The reaction mixture was cooled toambient temperature and then diluted with water (13 mL) and extractedwith EtOAc (2×17 mL). The combined organic extracts were dried (MgSO₄),filtered, concentrated in vacuo and purified by reverse phasechromatography (5-95% ACN/water) to afford the title compound (32.7 mg,51% yield). MS (apci) m/z=525.2 (M+H).

Example 193

4-(6-((1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of tert-butyl((1R,3s,5S)-8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate(31 mg, 0.0591 mmol) in EtOH (0.2 mL) was added 5 M HCl in iPrOH (414μL, 2.07 mmol). After stirring at ambient temperature for 4 h thereaction appeared complete by LCMS. The suspension was filtered, and thesolids were rinsed with Et₂O (3 mL) and dried in vacuo to afford thetitle compound (23.5 mg, 80% yield). MS (apci) m/z=425.1 (M+H).

Example 194

tert-butyl((1R,3r,5S)-8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate

In a pressure tube, a solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 75 mg, 0.202 mmol),tert-butyl ((1R,3r,5S)-8-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate(Intermediate R9; 104 mg, 0.242 mmol) and Pd(PPh₃)₄ (11.7 mg, 0.0101mmol) in dioxane (2 mL) was treated with 2 M Na₂CO_(3(aq)) (505 μL, 1.01mmol). The resulting reaction mixture was sparged with N2, sealed andheated at 90° C. overnight. The reaction mixture was cooled to ambienttemperature and then diluted with water (3 mL) and EtOAc (5 mL) andstirred. The resulting emulsion was filtered and the filtrate wasdiluted with additional water (10 mL) and extracted with EtOAc (2×15mL). The combined organic extracts were dried (MgSO₄), filtered,concentrated in vacuo and purified by reverse phase chromatography(5-95% ACN/water) to afford the title compound (25.9 mg, 24% yield). MS(apci) m/z=525.1 (M+H).

Example 195

4-(6-((1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of tert-butyl((1R,3r,5S)-8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate(24.8 mg, 0.0473 mmol) in EtOH (0.2 mL) was added 5 M HCl in iPrOH (407μL, 2.03 mmol). After stirring at ambient temperature overnight theresulting suspension was filtered, and the solids were rinsed with Et₂O(3 mL) and dried in vacuo to afford the title compound (16.8 mg, 71%yield). MS (apci) m/z=425.1 (M+H).

Example 196

4-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube a solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 44.9 mg, 0.121 mmol),1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin-4-ol(Intermediate R6; 81 mg, 0.133 mmol) and Pd(PPh₃)₄ (7.0 mg, 0.0061 mmol)in dioxane (1.2 mL) was treated with 2 M Na₂CO_(3(aq)) (303 μL, 0.61mmol). The resulting reaction mixture was sparged with nitrogen, sealedand heated at 90° C. overnight. After cooling to ambient temperature thereaction mixture was diluted with H₂O (3 mL) and EtOAc (5 mL), stirredfor 30 min and vacuum filtered, rinsing the collected solidssuccessively with water (20 mL) and EtOAc (20 mL). The isolated solidswere purified by reverse phase chromatography (5-75% ACN/water) toafford the title compound (14.0 mg, 29% yield). MS (apci) m/z=400.1(M+H).

Example 197

4-(6-(4-isobutoxypiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.0471 mmol) and 4-isobutoxypiperidine (22.2mg, 0.141 mmol) in DMSO (0.2 mL) were combined in a microwave vessel andsubjected to microwave irradiation at 125° C. for 1 h. The reactionmixture was directly purified by reverse phase chromatography (5-75%ACN/water) to provide the title compound (17.1 mg, 80% yield). MS (apci)m/z=456.1 (M+H).

Example 198

4-(6-(4-methoxypiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 17 mg, 0.0534 mmol) and 4-methoxypiperidine (18.5 mg,0.160 mmol) in DMSO (0.2 mL) were combined in a microwave vessel andsubjected to microwave irradiation at 125° C. for 30 min. The reactionmixture was directly purified by reverse phase chromatography (5-80%ACN/water). The chromatographic fractions containing the title compoundwere combined, concentrated in vacuo, and triturated with MTBE (1 mL) toyield the title product (12.4 mg, 56% yield). MS (apci) m/z=414.1 (M+H).

Example 199

4-(6-((1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube, a solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 35 mg, 0.094 mmol),(1R,3r,5S)-8-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-8-azabicyclo[3.2.1]octan-3-ol(Intermediate R7; 33 mg, 0.100 mmol) and Pd(PPh₃)₄ (5.4 mg, 0.0047 mmol)in dioxane (0.7 mL) was treated with 2 M Na₂CO_(3(aq)) (236 μL, 0.47mmol). The resulting reaction mixture was sparged with nitrogen, sealedand heated at 90° C. overnight. The reaction mixture was cooled toambient temperature, diluted with H₂O (7 mL) and extracted with DCM(2×15 mL). The combined organic extracts were concentrated and purifiedby silica chromatography (0-10% MeOH/EtOAc) to afford the title compound(3.5 mg, 9% yield). MS (apci) m/z=426.1 (M+H).

Example 200

4-(6-((1R,3r,5S)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of (1R,3r,5S)-3-methoxy-8-azabicyclo[3.2.1]octanehydrochloride (25 mg, 0.141 mmol) in MeOH (0.5 mL) was filtered througha basic resin (Stratospheres MP-HCO3, 100 mg, 1.8 mmol/g) and thefiltrate was concentrated in vacuo. The residue was taken up in DMSO(0.3 mL) and added to a microwave vessel containing4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.047 mmol). The resulting thick suspension wassubjected to microwave irradiation at 125° C. for 2 h. The reactionmixture was directly purified by reverse phase chromatography (5-90%ACN/water) to provide the title compound (10.7 mg, 52% yield). MS (apci)m/z=440.1 (M+H).

Example 201

tert-butyl(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

In a microwave vessel,4-(6-fluoropyridin-3-yl)-6-(1-methyl-H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 30 mg, 0.094 mmol) was treated with a solution oftert-butyl (4-methylpiperidin-4-yl)carbamate (61 mg, 0.28 mmol) in DMSO(0.4 mL). The resulting thick suspension was subjected to microwaveirradiation at 125° C. for 1 h. The reaction mixture was directlypurified by reverse phase chromatography (5-90% ACN/water) to afford thetitle compound (41 mg, 85% yield). MS (apci) m/z=513.1 (M+H).

Example 202

4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of tert-butyl(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate(40 mg, 0.0780 mmol) in EtOH (1 mL) was added 5 M HCl in iPrOH (2 mL, 10mmol). After stirring at ambient temperature overnight the resultingsuspension was filtered, and the solids were rinsed with Et₂O (3 mL) anddried in vacuo to afford the title compound (29.8 mg, 79% yield). MS(apci) m/z=413.1 (M+H).

Example 203

N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)isobutyramide

A solution of4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (8 mg, 0.016 mmol) in DMA (0.2 mL) was treated with DIEA(11.48 μL, 0.066 mmol) and isobutyryl chloride (2.6 μL, 0.025 mmol). Theresulting clear solution was stirred at ambient temperature overnight.The reaction mixture was diluted with water and the resulting mixturewas directly purified by chromatography (5-80% ACN/water) to afford thetitle compound (7.0 mg, 88% yield). MS (apci) m/z=483.1 (M+H).

Example 204

tert-butyl8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

In a microwave vessel,4-(6-fluoropyridin-3-yl)-6-(1-methyl-H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.047 mmol) and tert-butyl2,8-diazaspiro[4.5]decane-2-carboxylate (34.0 mg, 0.14 mmol) weresuspended in DMSO (0.4 mL). The resulting thick suspension was subjectedto microwave irradiation at 125° C. for 1 h. The reaction mixture wasdirectly purified by reverse phase chromatography (5-75% ACN/water) toafford the title compound (17.0 mg, 67% yield). MS (apci) m/z=539.2(M+H).

Example 205

4-(6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of tert-butyl8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate(16 mg, 0.030 mmol) in EtOH (0.1 mL) and DCM (0.1 mL) was added 5 M HClin iPrOH (208 μL, 1.04 mmol). After stirring at ambient temperature for2 h, the resulting suspension was concentrated in vacuo to afford thetitle compound (14.9 mg, 98% yield). MS (apci) m/z=439.1 (M+H).

Example 206

(R)-4-(6-(2-(2-hydroxy-3-methylbutanoyl)-2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(R)-2-hydroxy-3-methylbutanoic acid (1.7 mg, 0.015 mmol) and HATU (4.5mg, 0.012 mmol) were added sequentially to a solution of4-(6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.0098 mmol) and DIEA (22 μL, 0.12 mmol) in DMA(0.2 mL). After stirring at ambient temperature for 45 min, the reactionmixture was quenched with water (0.2 mL) and directly purified byreverse phase chromatography (5-80% ACN/water) to afford the titlecompound (3.1 mg, 59% yield). MS (apci) m/z=539.2 (M+H).

Example 207

4-(6-(2-isobutyryl-2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.01 mmol) and DIEA (10.2 μL, 0.058 mmol) in DMA(0.2 mL) was added isobutyryl chloride (1.5 μL, 0.015 mmol). Thereaction mixture was stirred at ambient temperature for 20 h and thendiluted with water (3 mL) and stirred for another 1 h. The resultingsuspension was vacuum filtered and the filter cake was rinsed with waterand dried in vacuo to afford the title compound (1.9 mg, 38% yield). MS(apci) m/z=509.2 (M+H).

Example 208

tert-butyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]decane-2-carboxylate

In a microwave vessel,4-(6-fluoropyridin-3-yl)-6-(1-methyl-H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.0471 mmol) and tert-butyl2,7-diazaspiro[4.5]decane-2-carboxylate (34.0 mg, 0.141 mmol) weresuspended in DMSO (0.2 mL). The resulting thick suspension was subjectedto microwave irradiation at 125° C. for 1 h. The reaction mixture wasdirectly purified by reverse phase chromatography (5-90% ACN/water) toafford the title compound (16.0 mg, 63% yield). MS (apci) m/z=539.2(M+H).

Example 209

4-(6-(2,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution of tert-butyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]decane-2-carboxylate(15 mg, 0.028 mmol) in EtOH (0.1 mL) and DCM (0.1 mL) was added 5 M HClin iPrOH (195 μL, 0.98 mmol). After stirring at ambient temperature for2 h the reaction mixture was concentrated in vacuo to afford the titlecompound (13.9 mg, 98% yield). MS (apci) m/z=439.1 (M+H).

Example 210

4-(6-(2-((R)-2-hydroxy-3-methylbutanoyl)-2,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(R)-2-hydroxy-3-methylbutanoic acid (1.7 mg, 0.015 mmol) and HATU (4.5mg, 0.012 mmol) were added sequentially to a solution of4-(6-(2,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.0098 mmol) and DIEA (10 μL, 0.059 mmol) in DMA(0.2 mL). After stirring at ambient temperature for 1 h, additional HATU(4 mg, 0.011 mmol) and (R)-2-hydroxy-3-methylbutanoic acid (2 mg, 0.018mmol) were added, and the reaction mixture was stirred for an additional90 min. The reaction mixture was directly purified by reverse phasechromatography (5-80% ACN/water) to afford the title compound (1:1diastereomeric mixture, 1.11 mg, 21% yield. MS (apci) m/z=539.2 (M+H))plus the individual diastereoisomers as listed in Examples 211 and 212below.

Example 211

4-(6-((S)-2-((R)-2-hydroxy-3-methylbutanoyl)-2,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The diastereomeric mixture prepared in Example 210 was purified byreverse phase chromatographic separation using 5-80% ACN/water as thegradient eluent. The higher R_(f) single diastereomeric isomer wasisolated to afford the title compound (0.25 mg, 4.7% yield). Theabsolute chiral sense for the spirocycle was arbitrarily assigned. MS(apci) m/z=539.2 (M+H).

Example 212

4-(6-((R)-2-((R)-2-hydroxy-3-methylbutanoyl)-2,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The diastereomeric mixture prepared in Example 210 was purified byreverse phase chromatographic separation using 5-80% ACN/water as thegradient eluent. The lower R_(f) single diastereomeric isomer wasisolated to afford the title compound (0.52 mg, 9.8% yield). Theabsolute chiral sense for the spirocycle was arbitrarily assigned. MS(apci) m/z=539.2 (M+H).

Example 213

4-(6-(2-isobutyryl-2,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of4-(6-(2,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.01 mmol) and DIEA (10.2 μL, 0.058 mmol) in DMA(0.2 mL) was added isobutyryl chloride (1.55 μL, 0.015 mmol). Thereaction mixture was stirred at ambient temperature for 20, then dilutedwith water (3 mL) and stirred for 3 h. The reaction mixture wasextracted with DCM, and the combined organic extracts were concentratedin vacuo then purified by reverse phase chromatography (5-80% ACN/water)to afford the title compound (4.3 mg, 86% yield). MS (apci) m/z=509.1(M+H).

Example 214

tert-butyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.047 mmol) and tert-butyl2,7-diazaspiro[3.5]nonane-2-carboxylate (32.0 mg, 0.14 mmol) weresuspended in DMSO (0.2 mL) in a microwave vessel. The resulting thicksuspension was subjected to microwave irradiation at 125° C. for 1 h.The reaction mixture was then directly purified by reverse phasechromatography (5-75% ACN/water) to afford the title compound (14.0 mg,57% yield). MS (apci) m/z=525.2 (M+H). ¹H NMR (CDCl₃) □ 8.63 (d, 1H),8.35 (d, 1H), 8.26 (s, 1H), 7.78 (s, 1H), 7.73 (dd, 1H), 7.68 (s, 1H),7.39 (d, 1H), 6.81 (s, 1H), 3.99 (s, 3H), 3.72 (s, 4H), 3.62 (m, 4H),1.85 (m, 4H), 1.46 (s, 9H).

Example 215

4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution of tert-butyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(13 mg, 0.025 mmol) in EtOH (0.1 mL) and DCM (0.1 mL) was added 5 M HClin iPrOH (198 μL, 0.99 mmol). After stirring at ambient temperature for2 h the resulting suspension was diluted with DCM and stirred for anadditional 2 d, then concentrated in vacuo to afford the title compound(11.0 mg, 89% yield). MS (apci) m/z=425.1 (M+H).

Example 216

(R)-4-(6-(2-(2-hydroxy-3-methylbutanoyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(R)-2-hydroxy-3-methylbutanoic acid (1.8 mg, 0.015 mmol), then HATU (4.6mg, 0.012 mmol) were added sequentially to a solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.010 mmol) and DIEA (11 μL, 0.060 mmol) in DMA(0.2 mL). After stirring at ambient temperature for 45 min the reactionmixture was quenched with water (0.2 mL) and directly purified byreverse phase chromatography (5-80% ACN/water) to afford the titlecompound (3.7 mg, 70% yield). MS (apci) m/z=525.1 (M+H). ¹H NMR (CDCl₃)□ 8.64 (d, 1H), 8.36 (d, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 7.75 (dd, 1H),7.68 (s, 1H), 7.39 (d, 1H), 6.83 (s, 1H), 3.99 (s, 3H), 3.91-3.98 (m,4H), 3.81 (d, 1H), 3.65 (m, 4H), 3.19 (d, 1H), 1.86-1.93 (m, 5H), 1.05(d, 3H), 0.88 (d, 3H).

Example 217

4-(6-(2-benzoyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5.4 mg, 0.011 mmol) in DMA (0.2 mL) was treated withDIEA (11.4 μL, 0.065 mmol) and benzoyl chloride (2.5 μL, 0.022 mmol).The reaction mixture was stirred at ambient temperature for 1 h and thenquenched with water (0.1 mL) and stirred for 2 d. The reaction mixturewas diluted with water (2 mL) and vacuum filtered. The isolated solidswere rinsed with water and dried in vacuo to afford the title compound(3.8 mg, 66% yield). MS (apci) m/z=529.2 (M+H).

The compounds in Table S were prepared according the method used for thesynthesis of Example 217, replacing benzoyl chloride with theappropriate acid chloride starting material.

TABLE S MS (apci) Ex # Structure Chemical Name m/z 218

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(2-(2-phenyl-acetyl)-2,7-diazaspiro[3.5]- nonan-7-yl)pyridin-3-yl)-pyrazolo[1,5-a]pyridine- 3-carbonitrile 543.2 (M + H) 219

4-(6-(2-(cyclopentane- carbonyl)-2,7-diazaspiro-[3.5]nonan-7-yl)pyridin- 3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 521.2 (M + H)

Example 220

4-(6-(2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (6.0 mg, 0.012 mmol) in DMA (0.2 mL) was treated withDIEA (13 μL, 0.072 mmol) and 1 M acetyl chloride in DCM (24 μL, 0.024mmol). After stirring at ambient temperature for 1 h the reaction wasquenched with water (0.1 mL) and directly purified by reverse phasechromatography (5-80% ACN/water) to afford the title compound (4.8 mg,85% yield). MS (apci) m/z=467.1 (M+H).

Example 221

4-(6-(2-isobutyryl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.010 mmol) in DMA (0.2 mL) was treated with DIEA(10.5 μL, 0.060 mmol) and isobutyryl chloride (1.6 μL, 0.015 mmol).After stirring at ambient temperature overnight the reaction wasquenched with water (3 mL) and stirred for an additional 3 h. Thereaction mixture was extracted with DCM and the combined organicextracts were concentrated in vacuo and directly purified by reversephase chromatography (5-80% ACN/water) to afford the title compound (4.4mg, 85% yield). MS (apci) m/z=495.1 (M+H).

Example 222

isopropyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

A solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5.0 mg, 0.010 mmol) in DMA (0.2 mL) was treated withDIEA (11 μL, 0.060 mmol) and 1 M isopropyl carbonochloridate in toluene(20 μL, 0.020 mmol). After stirring at ambient temperature for 4 h thereaction was quenched with water (0.1 mL), diluted with additional water(2 mL) and vacuum filtered, rinsing the solids with water. The solidswere dried in vacuo to afford the title compound (2.9 mg, 57% yield). MS(apci) m/z=511.2 (M+H). ¹H NMR (CDCl₃) □ 8.63 (d, 1H), 8.36 (d, 1H),8.26 (s, 1H), 7.79 (s, 1H), 7.74 (dd, 1H), 7.68 (s, 1H), 7.39 (d, 1H),6.81 (s, 1H), 4.91 (m, 1H), 3.99 (s, 3H), 3.75 (s, 4H), 3.63 (m, 4H),1.86 (m, 4H), 1.26 (d, 6H).

Example 223

tert-butyl2-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

In a microwave vessel, a mixture of tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate (85 mg, 0.38 mmol), DIEA (44 □L,0.25 mmol), and4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 40 mg, 0.13 mmol) in DMSO (1 mL) was subjected tomicrowave irradiation at 125° C. for 2 h. After cooling to ambienttemperature, the reaction mixture was directly purified by reverse-phasepreparative HPLC (10 to 80% acetonitrile/water) to give the titlecompound (12 mg, 18% yield). MS (apci) m/z=525.2 (M+H).

Example 224

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-morpholinopyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a microwave vessel, a mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 15 mg, 0.0471 mmol) and morpholine (12.3 μL, 0.128mmol) in DMSO (0.2 mL) was subjected to microwave irradiation at 125° C.for 1 h. The reaction mixture was directly purified by reverse phasechromatography (5-90% ACN/water). The chromatographic fractionscontaining title compound were combined, concentrated and trituratedwith MTBE (2 mL) to yield the title compound (4.0 mg, 22% yield). MS(apci) m/z=386.1 (M+H).

Example 225

(S)—N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)isobutyramideStep 1: Preparation of(S)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.100 g, 0.314 mmol), (S)-tert-butylpiperidin-3-ylcarbamate (0.252 g, 1.26 mmol) and potassium carbonate(0.174 g, 1.26 mmol) in DMSO (6.28 mL) was stirred at 110° C. overnight.The reaction mixture was then acidified to pH 7 with 1 M HCl_((aq)) andthe resulting suspension was vacuum filtered and rinsed with water. Theisolated solids were dissolved in 20% MeOH/DCM (5 mL), treated with 4MHCl in dioxane (1 mL) and concentrated in vacuo to afford the crudetitle compound as a solid, which was used directly in the next stepwithout further purification (0.106 g, 85% yield). MS (apci) m/z=399.2(M+H).

Step 2: Preparation of(S)—N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)isobutyramide

To a solution of(S)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(30 mg, 0.075 mmol) and DIEA (0.079 mL, 0.45 mmol) in DMA (2.5 mL) wasadded isobutyric acid (13.3 mg, 0.15 mmol) and HATU (57.3 mg, 0.15mmol). After stirring at ambient temperature overnight the reactionmixture was quenched with water and extracted with EtOAc (3×10 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silicachromatography (0-50% of 20% MeOH/DCM in EtOAc) to afford the titlecompound (14.4 mg, 39% yield). MS (apci) m/z=469.2 (M+H).

Example 226

(R)—N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)isobutyramideStep 1: Preparation of(R)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.100 g, 0.314 mmol), tert-butyl (R)-tert-butylpiperidin-3-yl-carbamate (0.252 g, 1.26 mmol) and potassium carbonate(0.174 g, 1.26 mmol) in DMSO (6.28 mL) was stirred at 110° C. overnight.The reaction mixture was acidified to pH 7 with 1 M HCl_((aq)) and theresulting suspension was vacuum filtered and rinsed with water. Theisolated solids were dissolved in 20% MeOH/DCM (5 mL), treated with 4 MHCl in dioxane (1 mL) and concentrated to afford the crude titlecompound as a solid, which was used directly in the next step withoutfurther purification. MS (apci) m/z=399.2 (M+H).

Step 2: Preparation of(R)—N-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)isobutyramide

To a solution of(R)-4-(6-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(30 mg, 0.075 mmol) and DIEA (0.066 mL, 0.38 mmol) in DMA (2.5 mL) wasadded isobutyric acid (13.3 mg, 0.15 mmol) and HATU (57.3 mg, 0.15mmol). After stirring at ambient temperature overnight the reactionmixture was quenched with water and extracted with EtOAc (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered, concentratedand purified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc)to afford the title compound (0.0131 g, 37% yield). MS (apci) m/z=469.2(M+H).

Example 227

(R)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylmorpholine-2-carboxamideStep 1: Preparation of(R)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)morpholine-2-carboxylicacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.100 g, 0.314 mmol) in DMSO (3.14 mL) was treatedwith (R)-morpholine-2-carboxylic acid hydrochloride (0.211 g, 1.26 mmol)and potassium carbonate (0.347 g, 2.51 mmol). The resulting thicksuspension was stirred and heated at 110° C. overnight. The reactionmixture was then acidified to pH 7 with the addition of 1 M HCl_((aq)).The resulting suspension was vacuum filtered rinsing solids with waterto afford the title compound (0.091 g, 68% yield). MS (apci) m/z=430.0(M+H).

Step 2: Preparation of(R)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylmorpholine-2-carboxamide

DIEA (0.051 mL, 0.29 mmol), propan-2-amine (6.9 mg, 0.12 mmol) and HATU(56 mg, 0.15 mmol) were added sequentially to a solution of(R)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)morpholine-2-carboxylicacid (25 mg, 0.058 mmol) in DMA (1.9 mL). After stirring at ambienttemperature overnight the reaction mixture was quenched with water andextracted with EtOAc (3×20 mL). The combined organic extracts were dried(Na₂SO₄), filtered, concentrated in vacuo and purified by silicachromatography (4 stepwise separations using from 0-50% of 20% MeOH/DCMin EtOAc to 0-10% MeOH/DCM) to afford the title compound (0.0069 g, 25%yield). MS (apci) m/z=471.2 (M+H).

Example 228

(S)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylmorpholine-2-carboxamideStep 1: Preparation of(S)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)morpholine-2-carboxylicacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.100 g, 0.31 mmol) in DMSO (3.14 mL) was treated with(S)-Morpholine-2-carboxylic acid hydrochloride (0.211 g, 1.26 mmol) andpotassium carbonate (0.347 g, 2.51 mmol). The resulting thick suspensionwas stirred and heated at 110° C. overnight. The reaction mixture wasacidified to pH 7 with 1 M HCl_((aq)). The resulting suspension wasvacuum filtered, rinsing solids with water to afford the title compound(0.100 g g, 74% yield). MS (apci) m/z=430.0 (M+H).

Step 2: Preparation of(S)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylmorpholine-2-carboxamide

DIEA (0.051 mL, 0.29 mmol), propan-2-amine (6.9 mg, 0.12 mmol) and HATU(55.3 mg, 0.146 mmol) were added sequentially to a solution(S)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)morpholine-2-carboxylicacid (25 mg, 0.058 mmol) in DMA (1.9 mL). After stirring at ambienttemperature overnight, the reaction mixture was quenched with water andextracted with EtOAc (3×20 mL). The combined organic extracts were dried(Na₂SO₄), filtered, concentrated and purified by silica chromatography(4 stepwise separations using from 0-50% of 20% MeOH/DCM in EtOAc to0-10% MeOH/DCM) to afford the title compound (5.6 mg, 20.0% yield). MS(apci) m/z=471.2 (M+H).

Example 229

(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-3-carboxamideStep 1: Preparation of(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-3-carboxylicacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 300 mg, 0.942 mmol) in DMSO (9.42 mL) was treated with(R)-piperidine-3-carboxylic acid (487 mg, 3.77 mmol) and potassiumcarbonate (521 mg, 3.77 mmol). The resulting thick suspension wasstirred and heated at 110° C. overnight. The reaction mixture was thenadjusted to pH 7 with saturated NaHCO_(3(aq)). The resulting suspensionwas vacuum filtered, rinsing solids with water to afford the titlecompound (0.272 g, 68% yield). MS (apci) m/z=428.2 (M+H).

Step 2: Preparation of(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-3-carboxamide

Propan-2-amine (6.9 mg, 0.12 mmol), DIEA (0.051 mL, 0.29 mmol), and HATU(55.3 mg, 0.15 mmol) were added sequentially to a solution(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-3-carboxylicacid (25 mg, 0.058 mmol) in DMA (2 mL). After stirring at ambienttemperature overnight, the reaction mixture was quenched with water andbrine and then extracted with EtOAc (3×20 mL). The combined organicextracts were dried (Na₂SO₄), filtered, concentrated and purified bysilica chromatography (0-50% of 20% MeOH/DCM in EtOAc) to afford thetitle compound (0.0147 g, 54% yield). MS (apci) m/z=469.2 (M+H).

Example 230

(S)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-3-carboxamide

Step 1: Preparation of(5)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-3-carboxylicacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 100 mg, 0.31 mmol) in DMSO (3 mL) was treated with(S)-piperidine-3-carboxylic acid (162 mg, 1.26 mmol) and potassiumcarbonate (174 mg, 1.26 mmol). The resulting suspension was stirred andheated at 110° C. overnight. The reaction mixture was then adjusted topH 7 with the addition of saturated NaHCO_(3(aq)). The resultingsuspension was vacuum filtered, rinsing solids with water to afford thetitle compound (32.9 mg, 26% yield). MS (apci) m/z=428.2 (M+H).

Step 2: Preparation of(5)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-3-carboxamide

Propan-2-amine (8.3 mg, 0.14 mmol), DIEA (0.061 mL, 0.35 mmol), and HATU(53.4 mg, 0.14 mmol) were added sequentially to a solution(5)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-3-carboxylicacid (30 mg, 0.070 mmol) in DMA (2.3 mL). After stirring at ambienttemperature overnight, the reaction mixture was quenched with water andbrine, and then extracted with EtOAc (3×20 mL). The combined organicextracts were dried (Na₂SO₄), filtered, concentrated and purified bysilica chromatography (0-50% of 20% MeOH/DCM in EtOAc) to afford thetitle compound (0.0204 g, 62% yield). MS (apci) m/z=469.2 (M+H).

Example 231

(S)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)piperidine-4-carboxamide

Step 1: Preparation of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 1.00 g, 3.14 mmol) in DMSO (31.4 mL) was treated withpiperidine-4-carboxylic acid (1.623 g, 12.57 mmol) and potassiumcarbonate (1.737 g, 12.57 mmol). The resulting thick suspension wasstirred and heated at 110° C. overnight. The reaction mixture was thenadjusted to pH 7 with saturated NaHCO_(3(aq)). The resulting suspensionwas vacuum filtered, rinsing solids with water to afford the titlecompound (1.077 g, 80% yield). MS (apci) m/z=428.2 (M+H).

Step 2: Preparation of(S)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)piperidine-4-carboxamide

(S)-1,1,1-trifluoropropan-2-amine (13.2 mg, 0.12 mmol), DIEA (0.051 mL,0.29 mmol), and HATU (44.5 mg, 0.12 mmol) were added sequentially to asolution1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid (25 mg, 0.058 mmol) in DMA (2 mL). After stirring at ambienttemperature overnight, the reaction mixture was quenched with water andbrine, and then extracted with EtOAc (3×10 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc) toafford the title compound (0.0151 g, 49% yield). MS (apci) m/z=523.2(M+H).

The compounds in Table T were prepared and purified according the methoddescribed for the synthesis of Example 231, replacing(S)-1,1,1-trifluoropropan-2-amine with the appropriate amine startingmaterials.

TABLE T MS (apci) Ex # Structure Chemical Name m/z 232

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (1-methoxypropan-2-yl)-piperidine-4-carboxamide 499.3 (M + H) 233

(R)-1-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin-2-yl)- N-(1,1,1-trifluoropropan-2-yl)piperidine-4-carboxamide 523.2 (M + H) 234

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (2-isopropoxyethyl)piperidine-4-carboxamide 513.3 (M + H) 235

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (3,3,3-trifluoro-2-methoxy-propyl)piperidine-4-carboxamide 553.2 (M + H) 236

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (2-methoxy-3-methylbutyl)-piperidine-4-carboxamide 527.3 (M + H) 237

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- ethoxypiperidine-4-carboxamide 471.2 (M +H) 238

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (3,3-difluorocyclobutyl)-piperidine-4-carboxamide 517.1 (M + H) 239

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (2-yl)-N-(2-methoxypropyl)-piperidine-4-carboxamide 499.1 (M + H) 240

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- ((1r,3r)-3-methoxycyclobutyl)-piperidine-4-carboxamide 511.2 (M + H) 241

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- ((1s,3s)-3-methoxycyclobutyl)-piperidine-4-carboxamide 511.2 (M + H)

Example 242

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(3,3,3-trifluoropropyl)piperidine-4-carboxamide

To a solution of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid (25 mg, 0.058 mmol) in DMF (2 mL) was added DIEA (0.0102 mL, 0.058mmol), 3,3,3-trifluoropropylamine (6.6 mg, 0.058 mmol), and HBTU (24.4mg, 0.064 mmol). After stirring at 40° C. overnight, the reactionmixture was quenched with water and brine and then extracted with EtOAc(3×10 mL). The combined organic extracts were dried (Na₂SO₄), filtered,concentrated and purified by silica chromatography (0-50% of 20%MeOH/DCM in EtOAc) to afford the title compound (0.017 g, 55% yield). MS(apci) m/z=523.1 (M+H).

Example 243

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2,2,2-trifluoroethyl)piperidine-4-carboxamide

To a solution1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid (0.025 g, 0.05849 mmol) in DMF (2 mL) was added DIEA (0.0102 mL,0.0585 mmol), 2,2,2-trifluoroethanamine (5.8 mg, 0.058 mmol), and HBTU(0.0244 g, 0.0643 mmol). After stirring at 40° C. overnight, thereaction mixture was quenched with water and brine and then extractedwith EtOAc (3×10 mL). The combined organic extracts were dried (Na₂SO₄),filtered, concentrated and purified by reverse phase chromatography(0-80% ACN/water) to afford the title compound (8.8 mg, 28% yield). MS(apci) m/z=509.1 (M+H).

Example 244

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutyl-N-methylpiperidine-4-carboxamide

N-methylisobutylamine (5.1 mg, 0.058 mmol), DIEA (0.010 mL, 0.058 mmol),and HBTU (24.4 mg, 0.064 mmol) were added sequentially to a solution1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid (25 mg, 0.058 mmol) in DMF (2 mL). After stirring at 30° C.overnight, the reaction mixture was quenched with water then extractedwith EtOAc (3×10 mL). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, concentrated in vacuo, and purified bysilica chromatography (0-50% of 20% MeOH/DCM in EtOAc) to afford thetitle compound (0.019 g, 64% yield). MS (apci) m/z=497.2 (M+H).

The compounds in Table U were prepared and purified according to themethod described for the synthesis of Example 244, replacingN-methylisobutylamine with the appropriate amine starting material.

TABLE U MS (apci) Ex # Structure Chemical Name m/z 245

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- (2-hydroxypropyl)-N-methyl-piperidine-4-carboxamide 499.2 (M + H) 246

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- isopropylpiperidine-4- carboxamide 469.2(M + H) 247

1-(5-(3-cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin-2-yl)-N- isopropyl-N-methylpiperidine-4-carboxamide 483.3 (M + H)

Example 248

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid (0.100 g, 0.23 mmol) in THF (4 mL) was cooled to −5° C. and thentreated with TEA (0.098 mL, 0.70 mmol) and ethyl carbonochloridate (0.11mL, 1.170 mmol). The resulting reaction mixture was stirred for 30 min,and then pyrrolidine (0.097 mL, 1.17 mmol) was then added. Afterstirring at −5° C. for 30 min the reaction mixture was stirred atambient temperature for 4 h, and then several more drops of TEA andpyrrolidine were added. The resulting reaction mixture was stirred atambient temperature for an additional 1 h, then quenched with water andextracted with EtOAc (3×10 mL). The combined organic extracts were driedover anhydrous Na₂SO₄, filtered, concentrated and purified by silicachromatography (0-50% of 20% MeOH/DCM in EtOAc) to afford the titlecompound (0.0045 g, 4% yield). MS (apci) m/z=481.1 (M+H).

Example 249

2-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-N-isopropylacetamideStep 1: Preparation of2-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)aceticacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.309 g, 0.97 mmol) in DMSO (9.7 mL) was treated with2-(piperidin-4-yl)acetic acid (0.556 g, 3.88 mmol) and potassiumcarbonate (0.537 g, 3.88 mmol). The resulting suspension was stirred andheated at 110° C. overnight. The reaction mixture was then adjusted topH 7 with saturated NaHCO_(3(aq)). The resulting suspension was vacuumfiltered, rinsing solids with water to afford the title compound (0.1924g, 45% yield). MS (apci) m/z=442.2 (M+H).

Step 2: Preparation of2-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-N-isopropylacetamide

Propan-2-amine (0.00669 g, 0.113 mmol), DIEA (0.049 mL, 0.283 mmol), andHATU (0.0431 g, 0.113 mmol) were added sequentially to a solution2-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)aceticacid (0.025 g, 0.0566 mmol) in DMA (1.89 mL). After stirring at ambienttemperature for 30 min, the reaction mixture was quenched with water andbrine and then extracted with EtOAc (3×10 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc) toafford the title compound (0.014 g, 51% yield). MS (apci) m/z=483.3(M+H).

Example 250

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3,3,3-trifluoropropyl)piperidine-4-carboxamideStep 1: Preparation of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid

A mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.45 g, 1.41 mmol), 4-methylpiperidine-4-carboxylicacid (0.81 g, 5.66 mmol) and potassium carbonate (0.78 g, 5.66 mmol) inDMSO (14 mL) was stirred at 110° C. overnight. The reaction mixture wasthen adjusted to pH 7 with saturated NaHCO_(3(aq)). The resultingsuspension was vacuum filtered and the solids were rinsed with water toafford the crude title product as a solid, which was directly used inthe next step without further purification. MS (apci) m/z=442.2 (M+H).

Step 2: Preparation of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methyl-N-(3,3,3-trifluoropropyl)piperidine-4-carboxamide

To a solution of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylicacid (25 mg, 0.056 mmol) in DMA (1.9 mL) was added3,3,3-trifluoropropylamine (12.8 mg, 0.11 mmol), DIEA (0.050 mL, 0.28mmol) and HATU (43.1 mg, 0.11 mmol). After stirring at ambienttemperature for 30 min, the reaction mixture was quenched with water andbrine and then extracted with EtOAc (3×10 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc) toafford the title compound (0.0234 g, 73% yield). MS (apci) m/z=537.2(M+H).

The compounds in Table V were prepared and purified according the methoddescribed for the synthesis of Example 250, replacing3,3,3-trifluoropropylamine with the appropriate amine starting material.

TABLE V MS (apci) Ex # Structure Chemical Name m/z 251

1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin- 2-yl)-N-isopropyl-4- methylpiperidine-4-carboxamide 483.3 (M + H) 252

1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin- 2-yl)-N-(1-methoxy- propan-2-yl)-4-methylpiperidine-4- carboxamide 513.3 (M + H) 253

(R)-1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]-pyridin-4-yl)pyridin- 2-yl)-4-methyl-N- (1,1,1-trifluoropropan-2-yl)piperidine-4- carboxamide 537.3 (M + H)

Example 254

Methyl1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate

A mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.060 g, 0.188 mmol), methyl4-methyl-4-piperidinecarboxylate (0.119 g, 0.754 mmol) and potassiumcarbonate (0.104 g, 0.754 mmol) in DMSO (1.88 mL) was heated overnightat 110° C. The pH of the reaction mixture was then adjusted to 7 withsaturated NaHCO_(3(aq)). The resulting suspension was vacuum filteredand rinsed with water and hexanes to afford the title compound (0.0451g, 50% yield). MS (apci) m/z=456.2 (M+H).

Example 255

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-(3,3,3-trifluoropropyl)piperidine-4-carboxamideStep 1: Preparation of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethylpiperidine-4-carboxylicacid

A mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.300 g, 0.942 mmol), 4-ethylpiperidine-4-carboxylicacid (0.593 g, 3.77 mmol) and potassium carbonate (0.521 g, 3.77 mmol)in DMSO (9.4 mL) was heated overnight at 110° C. The reaction mixture pHwas then adjusted to 7 with saturated NaHCO_(3(aq)). The resultingsuspension was vacuum filtered and rinsed with water to afford the titlecompound (0.176 g, 41% yield). MS (apci) m/z=456.2 (M+H).

Step 2: Preparation of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-(3,3,3-trifluoropropyl)piperidine-4-carboxamide

3,3,3-trifluoropropan-1-amine (12.4 mg, 0.11 mmol), DIEA (0.0478 mL,0.274 mmol), and HATU (41.7 mg, 0.110 mmol) were added sequentially to asolution1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethylpiperidine-4-carboxylicacid (25 mg, 0.055 mmol) in DMA (1.83 mL). After stirring at ambienttemperature for 1.5 h, the reaction mixture was quenched with water andbrine and then extracted with EtOAc (3×10 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc) toafford the title compound (0.0072 g, 24% yield). MS (apci) m/z=551.2(M+H).

The compounds in the following Table W were prepared and purifiedaccording the method described for the synthesis of Example 255,replacing 3,3,3-trifluoropropylamine with the appropriate amine startingmaterial.

TABLE W MS (apci) Ex # Structure Chemical Name m/z 256

1-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-ethyl-N-isopropyl-piperidine-4-carboxamide 497.2 (M + H) 257

(R)-1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-4-ethyl-N-(1,1,1-trifluoropropan-2- yl)piperidine-4-carboxamide 551.1 (M + H) 258

1-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin- 2-yl)-4-ethyl-N-(2-hydroxy-2-methylpropyl)piperidine- 4-carboxamide 527.3 (M + H) 549.3 (M + Na)

Example 259

(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(3,3,3-trifluoropropyl)pyrrolidine-3-carboxamideStep 1: Preparation of(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidine-3-carboxylicacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.300 g, 0.9425 mmol) in DMSO (9.425 mL) was treatedwith (R)-pyrrolidine-3-carboxylic acid (0.4340 g, 3.770 mmol) andpotassium carbonate (0.5210 g, 3.770 mmol). The resulting thicksuspension was stirred and heated overnight at 110° C. The reactionmixture was acidified to pH 7 with saturated NaHCO_(3(aq)). Theresulting suspension was diluted with water and brine and then vacuumfiltered, rinsing solids with water and hexanes to afford the titlecompound (0.31 g, 79% yield). MS (apci) m/z=414.1 (M+H).

Step 2: Preparation of(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(3,3,3-trifluoropropyl)pyrrolidine-3-carboxamide

3,3,3-trifluoropropan-1-amine (13.7 mg, 0.121 mmol), DIEA (0.0527 mL,0.30 mmol), and HATU (46.0 mg, 0.12 mmol) were added sequentially to asolution(R)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidine-3-carboxylicacid (25 mg, 0.060 mmol) in DMA (2.0 mL). After stirring at ambienttemperature overnight, the reaction mixture was quenched with water andbrine and then extracted with EtOAc (3×20 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc) toafford the title compound (18.5 mg, 59% yield). MS (apci) m/z=509.1(M+H).

The compounds in Table X were prepared and purified according the methoddescribed for the synthesis of Example 259, replacing3,3,3-trifluoropropan-1-amine with the appropriate amine startingmaterial.

TABLE X MS (apci) Ex # Structure Chemical Name m/z 260

(R)-6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(3-(pyrrolidine-1-carbonyl)pyrrolidin-1-yl)- pyridin-3-yl)pyrazolo[1,5-a]-pyridine-3-carbonitrile 467.2 (M + H) 261

(R)-1-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo-[1,5-a]pyridin-4-yl)pyridin-2- yl)-N-isopropylpyrrolidine-3- carboxamide455.2 (M + H)

Example 262

(S)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(3,3,3-trifluoropropyl)pyrrolidine-3-carboxamideStep 1: Preparation of(S)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidine-3-carboxylicacid

A solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.300 g, 0.9425 mmol) in DMSO (9.425 mL) was treatedwith (S)-pyrrolidine-3-carboxylic acid (0.434 g, 3.77 mmol) andpotassium carbonate (0.521 g, 3.77 mmol). The resulting thick suspensionwas stirred and heated at 110° C. overnight. The reaction mixture wasthen acidified to pH 7 with saturated NaHCO_(3(aq)). The resultingsuspension was diluted with water and brine and then vacuum filtered,rinsing the solids with water and hexanes to afford the title compound(0.523 g, quantitative yield). MS (apci) m/z=414.2 (M+H).

Step 2: Preparation of(S)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(3,3,3-trifluoropropyl)pyrrolidine-3-carboxamide

3,3,3-trifluoropropan-1-amine (0.0137 g, 0.121 mmol), DIEA (0.0527 mL,0.302 mmol), and HATU (0.0460 g, 0.121 mmol) were added sequentially toa solution(S)-1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)pyrrolidine-3-carboxylicacid (0.025 g, 0.0605 mmol) in DMA (2.02 mL). After stirring at ambienttemperature overnight, the reaction mixture was quenched with water andbrine and then extracted with EtOAc (3×10 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc) toafford the title compound (0.0141 g, 45% yield). MS (apci) m/z=509.2(M+H).

The compounds in Table Y were prepared and purified according the methoddescribed for the synthesis of Example 262, replacing3,3,3-trifluoropropan-1-amine with the appropriate amine startingmaterials.

TABLE Y MS (apci) Ex# Structure Chemical Name m/z 263

(S)-6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(3- (pyrrolidine-1-carbonyl)pyrrolidin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 467.2 (M + H) 264

(S)-1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N- isopropylpyrrolidine-3- carboxamide 455.2 (M + H)

Example 265

tert-Butyl4-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P14; 150 mg, 0.271 mmol),1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(133 mg, 0.543 mmol), Pd(PPh₃)₄ (31.4 mg, 0.0271 mmol) and 2 MNa₂CO_(3(aq)) (679 μL, 1.36 mmol) in dioxane (20 mL) was sparged withnitrogen, then sealed and heated at 100° C. overnight with stirring.After cooling to ambient temperature, the reaction mixture was dilutedwith water (10 mL) and filtered, and the solids were rinsed with waterand Et₂O and then air dried to afford the title compound (124 mg, 88%yield). MS (apci) m/z=521.2 (M+H).

Example 266

6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution of tert-butyl4-(5-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(120 mg, 0.231 mmol) in DCM (5 mL) was added 5 M HCl in iPrOH (231 μL,1.15 mmol). After stirring the resulting suspension at ambienttemperature overnight the reaction mixture was concentrated in vacuo toafford the title compound (111 mg, 98% yield). MS (apci) m/z=421.1(M+H).

Example 267

6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.020 mmol) in DMF (0.2 mL) was added3-methylbutanoyl chloride (3.7 mg, 0.030 mmol) and TEA (8.5 μL, 0.061mmol). The reaction mixture stirred at ambient temperature for 1 h andthen directly purified by reverse phase chromatography (0-60% ACN/water)to afford the title compound (3.4 mg, 33% yield). MS (apci) m/z=505.1(M+H).

Example 268

(R)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.020 mmol) in DMF (0.2 mL) was added3-methylbutanoyl chloride (3.7 mg, 0.030 mmol) and TEA (8.5 μL, 0.061mmol). The reaction mixture was stirred at ambient temperature for 1 hand then directly purified by reverse phase chromatography (0-60%ACN/water) to afford the title compound (3.4 mg, 33% yield). MS (apci)m/z=555.1 (M+H).

Example 269

(S)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of (S)-3-methoxypyrrolidine-1-carbonyl chloride

Triphosgene (129 mg, 0.436 mmol) was added in small portions over a 30min period to a suspension of (S)-3-methoxypyrrolidine hydrochloride(200 mg, 1.45 mmol) and DIEA (1.52 mL, 8.72 mmol) in DCM (3.48 mL). Theresulting mixture was stirred at ambient temperature for 3 h to providethe title compound as a fine suspension in DCM (0.25 M) which was usedin the next step without further purification.

Step 2: Preparation of(S)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (20 mg, 0.0405 mmol) and DIEA (42.4 μL, 0.243 mmol) inDCM (405 μL) was added (S)-3-methoxypyrrolidine-1-carbonyl chloride inDCM (0.25 M, 195 μL, 0.0486 mmol). The reaction was stirred at ambienttemperature for 3 d and then directly purified by reverse phasechromatography (0-75% ACN/water) to afford the title compound (1.8 mg,8% yield). MS (apci) m/z=548.1 (M+H).

Example 270

tert-Butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

tert-Butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P14; 150 mg, 0.271mmol),1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(113 mg, 0.543 mmol), Pd(PPh₃)₄ (31.4 mg, 0.0271 mmol) and 2 MNa₂CO_(3(aq)) (679 μL, 1.36 mmol) in dioxane (2 mL) were combined in apressure tube. The resulting reaction mixture was sparged with nitrogenand then sealed and heated at 100° C. overnight. The reaction mixturewas cooled to ambient temperature, then diluted with water (10 mL) andfiltered. The solids were washed with water (2×5 mL) and Et₂O (2×5 mL)and air dried to afford the title compound (108 mg, 82% yield). MS(apci) m/z=485.2 (M+H).

Example 271

6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution of tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(100 mg, 0.206 mmol) in DCM (5 mL) was added 5 M HCl in iPrOH (206 μL,1.03 mmol). After stirring at ambient temperature overnight theresulting suspension was filtered. The isolated solids were washed withEt₂O (2×5 mL) and then air dried to afford the title compound (95 mg,quantitative yield). MS (apci) m/z=385.1 (M+H).

Example 272

(R)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(R)-2-hydroxy-2-phenylacetic acid (7.5 mg, 0.049 mmol), HATU (25 mg,0.066 mmol), and TEA (23 μL, 0.16 mmol) were added sequentially to asolution of6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (15 mg, 0.033 mmol) in DMF (328 μL). After stirring atambient temperature for 1 h, the reaction mixture was purified byreverse phase chromatography (0-60% ACN/water) to afford the titlecompound (4.3 mg, 25% yield). MS (apci) m/z=519.2 (M+H).

Example 273

6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(4-(3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.22 mmol) in DMF (0.2 mL) was treated with3-methylbutanoyl chloride (4.0 mg, 0.033 mmol) and TEA (9.1 μL, 0.066mmol). After stirring at ambient temperature for 1 h, the reactionmixture was purified by reverse phase chromatography (0-60% ACN/water)to afford the title compound (5.7 mg, 56% yield). MS (apci) m/z=469.1(M+H).

Example 274

(S)-4-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (20 mg, 0.0437 mmol) and DIEA (45.7 μL, 0.262 mmol) inDCM (437 μL) was treated with (S)-3-methoxypyrrolidine-1-carbonylchloride (Example 269, Step 1, 0.25 M, 210 μL, 0.0525 mmol) and TEA (9.1μL, 0.066 mmol). After stirring at ambient temperature for 3 d, thereaction mixture was purified by reverse phase chromatography (0-75%ACN/water) to afford the title compound (2.9 mg, 13% yield). MS (apci)m/z=512.2 (M+H).

Example 275

tert-Butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

A mixture of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 250 mg, 0.673 mmol),tert-butyl4-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(299 mg, 0.741 mmol), Pd(PPh₃)₄ (19.5 mg, 0.0168 mmol), and 2 MK₂CO_(3(aq)) (2020 μL, 4.04 mmol) in dioxane (2693 μL) was sparged withnitrogen, then sealed and heated at 85° C. for 12 h. After cooling toambient temperature, the reaction mixture was partitioned between EtOAc(10 mL) and 2 M K₂CO_(3(aq)) (10 mL) and the phases were separated. Theemulsified organic phase was filtered through a PVDF (0.45 m) disc andthe filtrate was washed with brine. The combined organic extracts wereconcentrated in vacuo and the residue was purified directly by reversephase chromatography (5-75% ACN/water) to afford the title compound(0.11 g, 32% yield). MS (apci) m/z=499.2 (M+H).

Example 276

6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-6-piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution of tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3-methylpyridin-2-yl)piperazine-1-carboxylate(Example 275, 110 mg, 0.221 mmol) in DCM (4 mL) was added 5 M HCl iniPrOH (2206 μL, 11.0 mmol). The resulting suspension was stirred atambient temperature 1 h and then concentrated to near dryness in vacuo.The residue was treated with Et₂O, concentrated, and dried in vacuo toafford the title compound (104 mg, 98% yield). MS (apci) m/z=399.1(M+H).

Example 277

4-(6-(4-(3-hydroxy-3-methylbutanoyl)piperazin-1-yl)-5-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

3-hydroxy-3-methylbutanoic acid (4.51 mg, 0.0382 mmol) and HATU (14.5mg, 0.0382 mmol) were dissolved in DMA (159 μL) and the mixture wasstirred at ambient temperature for 10 min.6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 276, 15 mg, 0.0318 mmol) was added in oneportion followed by DIEA (27.7 μL, 0.159 mmol). After stirring for 45min, the reaction mixture was directly purified by reverse-phasechromatography (5-60% ACN/water) to afford the title compound (10.2 mg,62% yield). MS (apci) m/z=499.2 (M+H).

Example 278

(R)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)-5-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(R)-2-hydroxy-2-phenylacetic acid (5.8 mg, 0.038 mmol) and HATU (15 mg,0.038 mmol) were dissolved in DMA (159 μL) and stirred at ambienttemperature for 10 min.6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 276, 15 mg, 0.032 mmol) was added in oneportion followed by DIEA (28 μL, 0.16 mmol). After stirring for 90 min,the reaction was directly purified by reverse-phase chromatography(5-60% ACN/water) to afford the title compound (9.3 mg, 53% yield). MS(apci) m/z=533.1 (M+H).

Example 279

4-(6-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)-5-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 276, 15 mg, 0.0318 mmol) in DCM (159 μL) wasadded DIEA (27.7 μL, 0.159 mmol) followed by 3,3-dimethylbutanoylchloride (5.14 mg, 0.0382 mmol). After stirring for 45 min at ambienttemperature, the reaction mixture was directly purified by reverse-phasechromatography (C18, 5-75% ACN/water) to afford the title compound (12.7mg, 78% yield). MS (apci) m/z=497.1 (M+H).

Example 280

6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-6-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(5-methyl-6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 276, 20 mg, 0.0424 mmol) and DIEA (44.3 μL,0.255 mmol) in DriSolv® DCM (212 μL) was added dropwise to a 0° C.solution of triphosgene (6.30 mg, 0.0212 mmol) in DriSolv® DCM (212 μL)and the reaction mixture was stirred for 2 h, followed by the additionof pyrrolidine (3.02 mg, 0.0424 mmol) in one portion. The reactionmixture was stirred at ambient temperature for 2 d and then directlypurified by reverse-phase chromatography (C18, 5-60% ACN/water) toprovide the title compound (16.2 mg, 76% yield). MS (apci) m/z=496.2(M+H).

Example 281

6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride Step 1: Preparation of tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrimidin-2-yl)piperazine-1-carboxylate

3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 2.00 g, 5.39 mmol),(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidin-5-yl)boronic acid(2.49 g, 8.08 mmol), Pd(PPh₃)₄ (0.124 g, 0.108 mmol) and K₃PO₄ (3.43 g,16.2 mmol) were combined in dioxane (20 mL) in a pressure tube. Theresulting reaction mixture was sparged with nitrogen, sealed, and heatedat 100° C. overnight and then cooled to ambient temperature. Thereaction mixture was diluted with water (10 mL) and extracted withseveral portions of DCM in a PS frit. The combined DCM extracts wereconcentrated in vacuo and purified by silica chromatography (10-100%EtOAc/hexanes) to afford the title compound (0.148 g, 6% yield). MS(apci) m/z=386.1 (M+H-Boc).

Step 2: Preparation of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(140 mg, 0.289 mmol) in DCM (10 mL) was added 5 M HCl in iPrOH (173 μL,0.867 mmol). The reaction mixture was stirred at ambient temperature for6 h and then diluted with Et₂O (10 mL). The resulting suspension wasvacuum filtered and the solids were washed with Et₂O and air dried toafford the title compound (92 mg, 70% yield). MS (apci) m/z=386.0 (M+H).

Example 282

(R)-4-(2-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (12 mg, 0.262 mmol) in DMF (105 μL) was treatedsequentially with (R)-2-hydroxy-2-phenylacetic acid (0.0133 g, 0.151mmol), HATU (19.9 mg, 0.0524 mmol), and TEA (18.2 μL, 0.131 mmol). Theresulting reaction mixture was stirred at ambient temperature overnightand then directly purified by reverse phase chromatography (0-65%ACN/water) to afford the title compound (10.8 mg, 79.4% yield). MS(apci) m/z=520.1 (M+H).

Example 283

6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(4-(3-methylbutanoyl)piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.22 mmol) in DMF (0.2 mL) was treated with TEA(9.1 μL, 0.065 mmol) and 3-methylbutanoyl chloride (3.9 mg, 0.033 mmol).The resulting reaction mixture was stirred at ambient temperatureovernight and then directly purified by reverse phase chromatography(0-60% ACN/water) to afford the title compound (3.1 mg, 30% yield). MS(apci) m/z=470.1 (M+H).

Example 284

(R)-4-(2-(4-(2-methoxy-2-phenylacetyl)piperazin-1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.22 mmol) in DMF (87 μL) was added(R)-2-methoxy-2-phenylacetic acid (11 mg, 0.065 mmol), DMAP (2.7 mg,0.022 mmol), DIEA (11 μL, 0.065 mmol) and EDC-HCl (17 mg, 0.087 mmol).The resulting reaction mixture was stirred at ambient temperatureovernight and then purified directly using reverse phase chromatography(0-65% ACN/water) to provide the title compound (6.8 mg, 58% yield). MS(apci) m/z=534.1 (M+H).

Example 285

(R)-4-(2-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.022 mmol) and EDC-HCl (17 mg, 0.087 mmol) inDMF (0.2 mL) was treated with (R)-2-hydroxy-3-methylbutanoic acid (7.7mg, 0.065 mmol), DMAP (2.7 mg, 0.022 mmol) and TEA (15 μL, 0.11 mmol).The resulting reaction mixture was stirred at ambient temperatureovernight and then purified directly using reverse phase chromatography(0-55% ACN/water) to provide the title compound (6.2 mg, 59% yield). MS(apci) m/z=486.1 (M+H).

Example 286

(S)-4-(2-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (20 mg, 0.044 mmol) and DIEA (46 μL, 0.26 mmol) in DCM(436 μL) was treated with (S)-3-methoxypyrrolidine-1-carbonyl chloride(Example 269, Step 1, 0.25 M, 209 μL, 0.052 mmol). The reaction wasstirred for 3 d at ambient temperature and directly purified by reversephase chromatography (0-75% ACN/water) to provide the title compound(4.5 mg, 20% yield). MS (apci) m/z=513.1 (M+H).

Example 287

6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(piperazin-1-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate

3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 100 mg, 0.269 mmol),tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperazine-1-carboxylate(105 mg, 0.269 mmol), Na₂CO₃ (143 mg, 1.35 mmol) and Pd(PPh₃)₄ (15.6 mg,0.0135 mmol) were combined in 4:1 dioxane/water (4 mL). The resultingreaction mixture was purged with Argon for 10 min and then heated at 90°C. under continued atmosphere of Argon overnight. The reaction mixturewas cooled to ambient temperature and then concentrated in vacuo. Thecrude residue was partitioned between DCM (50 mL) and water (50 mL) andthe combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to afford the title compound. MS (apci) m/z=486.2(M+H). The crude product was used directly in the next step withoutfurther purification.

Step 2: Preparation of6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(piperazin-1-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A solution of tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)piperazine-1-carboxylate(131 mg, 0.270 mmol) in DCM (4 mL) was treated with TFA (2 mL) atambient temperature. The resulting mixture was stirred overnight atambient temperature and then concentrated in vacuo. The crude residuewas dissolved in a solution of 20% iPrOH in DCM (50 mL) and extractedwith 10% NaHCO_(3(aq)) (50 mL). The aqueous layer was separated and thenextracted with a solution of 20% iPrOH in DCM (50 mL). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo. The resulting crude residue was purified twice, first by silicachromatography (eluting with 10% MeOH in DCM and then with 5% MeOH inDCM containing 2% TEA), then by reverse phase chromatography (5-95%ACN/water) to afford the title compound (0.051 g, 49% yield). MS (apci)m/z=386.0 (M+H).

Example 288

(R)-4-(5-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(piperazin-1-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(20 mg, 0.052 mmol) in DMF (4 mL) was treated sequentially withD-(−)-Mandelic acid (11.84 mg, 0.07784 mmol), HATU (19.9 mg, 0.0524mmol), and DIEA (90.38 μL, 0.5189 mmol). The resulting reaction mixturewas stirred at ambient temperature overnight and then partitionedbetween water (50 mL) and EtOAc (50 mL). The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica chromatography (1:4 hexanes/EtOAc) toafford the title compound (0.016 g, 60% yield). MS (apci) m/z=520.2(M+H).

Example 289

(S)-4-(5-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(piperazin-1-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(32 mg, 0.083 mmol) and DIEA (87 μL, 0.50 mmol) in DriSolv® DCM (415 μL)was cooled to 0° C. and then added dropwise to a 0° C. solution oftriphosgene (11 mg, 0.037 mmol) in DriSolv® DCM (415 μL). After stirringthe reaction mixture for 0.5 h at 0° C., (S)-3-methoxypyrrolidinehydrochloride (11 mg, 0.083 mmol) was added in one portion, and thereaction was stirred at ambient temperature overnight. The reactionmixture was directly purified by silica chromatography (5% MeOH in EtOAcas eluent) to afford the title compound (0.023 g, 54% yield). MS (apci)m/z=513.3 (M+H).

Example 290

tert-Butyl4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate

3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 25 mg, 0.0673 mmol),tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(34.0 mg, 0.0875 mmol), Pd(PPh₃)₄ (7.78 mg, 0.00673 mmol) and 2 MNa₂CO_(3(aq)) (362 μL, 0.723 mmol) were combined in dioxane (0.3 mL) ina pressure tube. The resulting reaction mixture was sparged withnitrogen and then sealed and heated at 100° C. for 2 h. The reactionmixture was cooled to ambient temperature, then diluted with brine (1mL) and extracted with several portions of DCM. The combined DCMextracts were concentrated in vacuo and purified directly by reversephase chromatography (0-70% ACN/water) to afford the title compound (28mg, 72% yield). MS (apci) m/z=215.1 (M+H-Boc).

Example 291

6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a solution tert-butyl4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate(28 mg, 0.049 mmol) in DCM (1 mL) was added 5 M HCl in iPrOH (49 μL,0.24 mmol). The reaction was stirred at ambient temperature overnightand then vacuum filtered. The isolated solids were washed with DCM andEt₂O and air dried to afford the title compound (19 mg, 86% yield). MS(apci) m/z=384.1 (M+H).

Example 292

4-(4-(4-(2-methoxyacetyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.0219 mmol) in DCM (0.1 mL) was treated withTEA (30.5 μL, 0.219 mmol) and 2-methoxyacetyl chloride (4.76 mg, 0.0438mmol). The resulting reaction mixture was stirred at ambient temperaturefor 30 min, then concentrated in vacuo and directly purified by reversephase chromatography (0-70% ACN/water) to afford the title compound (5.2mg, 52.1% yield). MS (apci) m/z=456.1 (M+H).

Example 293

4-(4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (35 mg, 0.077 mmol) in DCM (0.5 mL) was treated with2-chloro-2-oxoethyl acetate (31.41 mg, 0.23 mmol) and TEA (30.5 μL,0.219 mmol. The resulting reaction mixture was stirred at ambienttemperature for 30 min, then MeOH (0.2 mL) and NaOH (383.46 μL, 0.383mmol) were added and the reaction was stirred at ambient temperatureovernight. The reaction was quenched with water (1 mL) and extractedwith several portions of DCM in a PS frit. The DCM extracts wereconcentrated in vacuo and the crude residue was dissolved in 1:1DCM/MeOH (1 mL) and treated with 5 M HCl in iPrOH (46 μL, 0.23 mmol).The resulting mixture was concentrated in vacuo and the residue wastaken up in DCM (2 mL) and sonicated. The suspension was vacuum filteredand the solids were successively rinsed with DCM (2 mL) and Et₂O (3×2mL) and then dried in vacuo to afford the title compound (27 mg, 80%yield). MS (apci) m/z=442.0 (M+H).

Example 294

4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (12 mg, 0.026 mmol) in DCM (1 mL) was treated with3,3-dimethylbutanoyl chloride (11 mg, 0.079 mmol) and TEA (18 μL, 0.13mmol). The resulting reaction mixture was stirred at ambient temperaturefor 1 h and then quenched with water (1 mL) and extracted with severalportions of DCM (3×5 mL) in a PS frit. The combined DCM extracts wereconcentrated in vacuo and then taken up in MeOH (0.5 mL) and sonicated.The resulting suspension was vacuum filtered and the solids were rinsedwith Et₂O (3×2 mL) to afford the title compound (10 mg, 79% yield). MS(apci) m/z=482.2 (M+H).

The compounds in Table Z were prepared and purified according to themethod described for the synthesis of Example 294, replacing3,3-dimethylbutanoyl chloride for the appropriate acid chloride startingmaterial.

TABLE Z MS (apci) Ex# Structure Chemical Name m/z 295

4-(4-(4-acetylpiperazin- 1-yl)phenyl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 426.1 (M + H) 296

4-(4-(4-(2-(dimethyl- amino)acetyl)piperazin- 1-yl)phenyl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 469.1(M + H)

Example 297

6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride (6 mg, 0.014 mmol) in DCM (0.2 mL) was added TEA (10 μL,0.071 mmol) followed by methanesulfonyl chloride (29 μL, 0.029 mmol).The mixture was stirred at ambient temperature for 1 h, thenconcentrated in vacuo and purified by reverse phase chromatography(0-70% ACN/water) to provide the title compound (6.2 mg, 94% yield). MS(apci) m/z=462.1 (M+H).

Example 298

Methyl4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate

6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.022 mmol), methyl carbonochloridate (6.2 mg,0.066 mmol) and TEA (18 μL, 0.13 mmol) were combined in DCM (0.1 mL) andstirred at ambient temperature for 30 min. The reaction mixture wasconcentrated in vacuo and purified by reverse phase chromatography(0-60% ACN/water) to afford the title compound (5.1 mg, 53% yield). MS(apci) m/z=442.2 (M+H).

Example 299

4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-N-methylpiperazine-1-sulfonamide

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (10 mg, 0.0219 mmol) in DCM (0.2 mL) was treated withTEA (30.5 μL, 0.219 mmol) and methylsulfamoyl chloride (110 μL, 0.110mmol) and stirred at ambient temperature overnight. The resultingmixture was concentrated in vacuo and purified by reverse phasechromatography (0-70% ACN/water) to afford the title compound (1.2 mg,12% yield). MS (apci) m/z=477.2 (M+H).

Example 300

tert-butyl4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-1-carboxylate

A solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 30 mg, 0.0808 mmol) indioxane (0.8 mL) was treated with tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate(Intermediate R10; 46.9 mg, 0.121 mmol), 2 M Na₂CO_(3(aq)) (202 μL,0.404 mmol) and Pd(PPh₃)₄ (4.67 mg, 0.00404 mmol) in a pressure tube.The resulting reaction mixture was sparged with nitrogen, sealed andheated at 90° C. overnight. The reaction mixture was cooled to ambienttemperature and then diluted with water (5 mL) and stirred well. Theresulting suspension was diluted with additional water (3 mL) and theaqueous suspension was extracted with DCM (2×10 mL). The combinedorganic extracts were concentrated in vacuo and purified by silicachromatography (25-100% EtOAc/hexanes) to afford the title compound(23.4 mg, 60% yield). MS (apci) m/z=383.1 (M+H-Boc). ¹H NMR (CDCl₃) δ8.65 (d, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.53 (m, 2H),7.45 (d, 1H), 7.38 (m, 2H), 4.28 (m, 2H), 4.00 (s, 3H), 2.83 (m, 2H),2.76 (m, 1H), 1.91 (m, 2H), 1.69 (m, 2H), 1.49 (s, 9H).

Example 301

6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

To a suspension of tert-butyl4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperidine-1-carboxylate(22.3 mg, 0.0462 mmol) in EtOH (0.2 mL) was added 5 M HCl in iPrOH (305μL, 1.52 mmol). After stirring at ambient temperature 2 h, the resultingsuspension was vacuum filtered, and the solids were rinsed with Et₂O (2mL) and dried in vacuo to afford the title compound (17.0 mg, 81%yield). MS (apci) m/z=383.1 (M+H).

Example 302

4-(4-(1-(3,3-dimethylbutanoyl)piperidin-4-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (8 mg, 0.0176 mmol) in DCM (0.4 mL) was treated with3,3-dimethylbutanoyl chloride (3.68 μL, 0.0264 mmol) and DIEA (12.2 μL,0.0703 mmol), and the resulting solution was stirred at ambienttemperature for overnight. The reaction was quenched with MeOH (0.2 mL),then partially concentrated in vacuo and purified by silicachromatography (0-100% EtOAc/hexanes) to afford the title compound (6.5mg, 77% yield). MS (apci) m/z=481.2 (M+H).

Example 303

4-(4-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (8 mg, 0.018 mmol) in DCM (0.4 mL) was treated with2-(dimethylamino)acetyl chloride hydrochloride (4.2 mg, 0.026 mmol) andDIEA (18 μL, 0.11 mmol), and the resulting solution was stirred atambient temperature overnight. The reaction was quenched with MeOH (0.2mL), partially concentrated in vacuo, and then purified by reverse phasechromatography (5-75% MeCN/water) to afford the title compound (2.4 mg,29% yield). MS (apci) m/z=468.1 (M+H).

Example 304

(S)-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate (Intermediate P16; 0.030 g, 0.055 mmol) indioxane (4 mL) was treated with(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol(0.021 g, 0.082 mmol) and 2 M K₂CO_(3(aq)) (0.055 mL, 0.11 mmol). Theresulting reaction mixture was purged with N₂ for 5 min, and then X-Phos(0.0052 g, 0.011 mmol) and Pd₂(dba)₃ (0.0025 g, 0.0027 mmol) were addedto the reaction mixture. The mixture was purged with nitrogen for anadditional 5 min then heated at 80° C. under a nitrogen atmosphereovernight. The reaction mixture was cooled to ambient temperature, thendiluted with water (5 mL) and extracted with EtOAc (3×5 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,concentrated in vacuo and purified by silica chromatography (0-50% 20%MeOH/DCM in EtOAc) to afford the title compound (5.4 mg, 18% yield). MS(apci) m/z=526.2 (M+H).

Example 305

(R)-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate (0.030 g, 0.0546 mmol) in dioxane (4 mL) wastreated with(R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol(0.0206 g, 0.0819 mmol) and 2 M K₂CO_(3(aq)) (0.0546 mL, 0.109 mmol).The resulting reaction mixture was purged with nitrogen for 5 min, andthen X-Phos (0.00520 g, 0.0109 mmol) and Pd₂(dba)₃ (0.00250 g, 0.00273mmol) were added. The reaction mixture was purged with nitrogen for anadditional 5 min and then heated overnight at 80° C. under a nitrogenatmosphere. The reaction mixture was cooled to ambient temperature, thendiluted with water (5 mL) and extracted with EtOAc (3×5 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered, concentratedand purified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc)to afford the title compound (0.0161 g, 54% yield). MS (apci) m/z=526.2(M+H).

Example 306

(R)-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate (Intermediate P16; 0.200 g, 0.3639 mmol) indioxane (15 mL) was treated with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.1606 g, 0.5459 mmol) and 2 M K₂CO_(3(aq)) (0.3639 mL, 0.7278 mmol).The resulting reaction mixture was purged with nitrogen for 5 min, andthen X-Phos (0.03470 g, 0.07278 mmol) and Pd₂(dba)₃ (0.01666 g, 0.01820mmol) were added. The reaction mixture was purged with nitrogen for anadditional 5 min and then heated overnight at 80° C. under a nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthen diluted with water (20 mL) and extracted with EtOAc (3×50 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silicachromatography (0-50% of 20% MeOH/DCM in EtOAc). The fractionscontaining the desired mass for tert-butyl4-(3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazole-1-carboxylate(by LCMS) were combined, concentrated in vacuo, dissolved in 20%MeOH/DCM (25 mL), treated with 4 N HCl in dioxane (5 mL) and stirredovernight. The reaction mixture was quenched with saturatedNaHCO_(3(aq)) and extracted with 10% MeOH/DCM (3×50 mL). The organic andaqueous extracts were treated separately. The organic extracts werecombined, dried over anhydrous Na₂SO₄, filtered and reserved. Theaqueous layer was filtered and the insoluble solid collected wasseparately washed with MeOH (50 mL) and DCM (50 mL). The organicfiltrates from both the original extraction and the solid wash werecombined and concentrated in vacuo to afford the title compound (0.1663g, 98% yield). MS (apci) m/z=468.1 (M+H).

Step 2: Preparation of(R)-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.030 g, 0.06416 mmol) and (S)-3-bromo-2-methylpropan-1-ol (0.0134 mL,0.1283 mmol) in DMF (1.283 mL, 0.0645 mmol) was treated with Cs₂CO₃(0.04181 g, 0.128 mmol). The resulting mixture was heated at 80° C. andstirred overnight. After cooling to ambient temperature, the reactionmixture was diluted with water (10 mL), pH adjusted to 8 with 1 NHCl_((aq)), then extracted with EtOAc (3×15 mL). The combined organicextracts were washed with brine, dried (Na₂SO₄), filtered, concentratedand purified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc)to afford the title compound (0.0131 g, 38% yield). MS (apci) m/z=540.2(M+H).

Example 307

(S)-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.030 g, 0.0645 mmol) and (R)-3-bromo-2-methylpropan-1-ol (0.01344 mL,0.1283 mmol) in DMF (1.283 mL, 0.0645 mmol) was treated with Cs₂CO₃(0.04181 g, 0.128 mmol). The resulting mixture was heated at 80° C. andstirred overnight. After cooling to ambient temperature, the reactionmixture was diluted with water (10 mL), the pH adjusted to 8 with 1 NHCl_((aq)), and extracted with EtOAc (3×15 mL). The combined organicextracts were washed with brine, dried (Na₂SO₄), filtered, concentratedand purified by silica chromatography (0-50% of 20% MeOH/DCM in EtOAc)to afford the title compound (0.0133 g, 38% yield). MS (apci) m/z=540.2(M+H).

Example 308

4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-imidazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube,3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate (20 mg, 0.036 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole(15 mg, 0.073 mmol), PdCl₂(dppf).CH₂Cl₂ (3.0 mg, 0.0036 mmol) and Cs₂CO₃(59 mg, 0.18 mmol) were combined in dioxane (0.2 mL), sparged with N2,sealed and heated at 100° C. for 3 h. After cooling to ambienttemperature, the reaction mixture was diluted with water (1 mL) andextracted with DCM (3×5 mL). The combined organic extracts wereconcentrated in vacuo and purified by reverse phase chromatography(0-75% ACN/water with 0.1% HCl) to afford the title compound (2 mg, 11%yield). MS (apci) m/z=482.3 (M+H).

Example 309

4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube,3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate (Intermediate P16; 20 mg, 0.036 mmol),1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15mg, 0.073 mmol), Pd(PPh₃)₄ (4.2 mg, 0.0036 mmol) and 2 M Na₂CO_(3(aq))(91 μL, 0.18 mmol) were combined in dioxane (0.2 mL), sparged with N2,sealed and heated at 100° C. for 3 h. After cooling to ambienttemperature and stirring overnight, the reaction mixture was dilutedwith water (1 mL) and extracted with DCM (3×5 mL). The combined organicextracts were concentrated in vacuo and purified by reverse phasechromatography (0-95% ACN/water) to afford the title compound (4.6 mg,26% yield). MS (apci) m/z=482.1 (M+H).

Example 310

4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(5-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube,3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-6-yltrifluoromethanesulfonate (Intermediate P16; 20 mg, 0.036 mmol),5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15mg, 0.073 mmol), Pd(PPh₃)₄ (4.2 mg, 0.0036 mmol) and 2 M Na₂CO_(3(aq))(91 μL, 0.18 mmol) were combined in dioxane (0.2 mL). The reactionmixture was sparged with N2, sealed and heated at 100° C. for 3 h andthen stirred at ambient temperature overnight. The reaction mixture wasdiluted with water (1 mL) and extracted with DCM (3×5 mL). The combinedorganic extracts were concentrated in vacuo then triturated with MeOH(0.2 mL). The resulting suspension was vacuum filtered, and the isolatedsolids were rinsed with Et₂O and air dried to afford the title compound(7 mg, 40% yield). MS (apci) m/z=482.1 (M+H).

Example 311

tert-Butyl4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube,6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P7; 750 mg, 2.17 mmol),(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (998mg, 3.25 mmol), Pd(PPh₃)₄ (250 mg, 0.217 mmol) and 2 M Na₂CO_(3(aq))(5.42 mL, 10.8 mmol) were combined in dioxane (20 mL). The resultingreaction mixture was sparged with nitrogen, then sealed and heated at100° C. overnight. After cooling to ambient temperature the reactionmixture was diluted with water (10 mL) and extracted with severalportions of DCM in a PS frit. The combined organic extracts wereconcentrated in vacuo and purified by silica chromatography (10-100%EtOAc/hexanes) to afford the title compound (826 mg, 83% yield). MS(apci) m/z=460.1 (M+H).

Example 312

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride

To a solution of tert-butyl4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(820 mg, 1.78 mmol) in DCM (5 mL) was added 5 M HCl in iPrOH (1784 μL,8.92 mmol). The reaction was stirred at ambient temperature overnight.The resulting suspension was vacuum filtered and the solids were washedwith Et₂O (2×5 mL) then air dried to afford the title compound (640 mg,99% yield). MS (apci) m/z=360.1 (M+H).

Example 313

(R)-2-hydroxy-1-(4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-phenylethanone

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (24.6 mg, 0.0568984 mmol) in DCM (1.2 mL) was treatedwith D-(−)-Mandelic acid (12.99 mg, 0.08535 mmol), HATU (21.63 mg,0.05690 mmol) and DIEA (99.11 μL, 0.5690 mmol). The resulting reactionmixture was stirred at ambient temperature overnight, then concentratedin vacuo and purified by silica chromatography (10-80% DCM/acetone) toafford the title compound (13.2 mg, 47% yield). MS (apci) m/z=494.1(M+H).

The compounds in Table AA were prepared in a similar fashion asdescribed for the synthesis of Example 313, replacing D-(−)-Mandelicacid with the appropriate acid starting material.

TABLE AA MS (apci) Ex# Structure Chemical Name m/z 314

2-(2,6- difluorophenyl)-1-(4- (5-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4- yl)pyridin-2- yl)piperazin-1- yl)ethanone514.1 (M + H) 315

(2,6- difluorophenyl)(4-(5- (6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2- yl)piperazin-1- yl)methanone 500.1 (M + H)316

(R)-2-hydroxy-1-(4- (5-(6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4- yl)pyridin-2- yl)piperazin-1-yl)-2- (p-tolyl)ethanone 508.1(M + H) 317

2-(2,4- difluorophenyl)-2- hydroxy-1-(4-(5-(6- (1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4- yl)pyridin-2- yl)piperazin-1- yl)ethanone530.1 (M + H) 318

2-(2,6- difluorophenyl)-2- hydroxy-1-(4-(5-(6- (1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4- yl)pyridin-2- yl)piperazin-1- yl)ethanone530.1 (M + H) 319

2-(3,5- difluorophenyl)-2- hydroxy-1-(4-(5-(6- (1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4- yl)pyridin-2- yl)piperazin-1- yl)ethanone530.1 (M + H)

Example 320

(R)-2-(2-chlorophenyl)-2-hydroxy-1-(4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)ethanone

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (17.4 mg, 0.040 mmol) in DMF (1.2 mL) was treated with(R)-(−)-2-chloromandelic acid (9.0 mg, 0.048 mmol), HATU (18.4 mg, 0.048mmol) and DIEA (70 μL, 0.40 mmol). The resulting reaction mixture wasstirred at ambient temperature overnight and then diluted with EtOAc (10mL). The reaction mixture was washed with water (2×10 mL) and brine (10mL), and the combined organic extracts were dried over anhydrous Na₂SO₄,filtered, concentrated in vacuo and purified by silica chromatography(10-80% DCM/acetone) to afford the title compound (8.6 mg, 40% yield).MS (apci) m/z=528.1 (M+H).

The compounds in Table BB were prepared according the method describedfor the synthesis of Example 320, replacing D-(−)-Mandelic acid with theappropriate acid starting material.

TABLE BB MS (apci) Ex# Structure Chemical Name m/z 321

(R)-2-(2-fluorophenyl)- 2-hydroxy-1-(4-(5-(6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)pyridin- 2-yl)piperazin-1- yl)ethanone512.2 (M + H) 322

(R)-2-(3-chlorophenyl)- 2-hydroxy-1-(4-(5-(6- (1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)pyridin- 4-yl)piperazin-1- yl)ethanone528.1 (M + H)

Example 323

N-methyl-4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-phenylpiperazine-1-carboxamide

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (50.4 mg, 0.117 mmol) and DIEA (122 μL, 0.699 mmol) inDriSolv® DCM (0.5 mL) was cooled to 0° C. and then added dropwise to a0° C. solution of triphosgene (13.8 mg, 0.0466 mmol) in DriSolv® DCM(1.1 mL). After stirring the reaction mixture for 1 h at 0° C.,N-methylaniline (13.9 μL, 0.128 mmol) was added in one portion, and thereaction was stirred at ambient temperature overnight. The reactionmixture was diluted with DCM and washed with saturated NaHCO_(3(aq)).The combined organic extracts were dried (Na₂SO₄), filtered,concentrated and purified by silica chromatography (10-80% DCM/acetone)to afford the title compound (13.1 mg, 23% yield). MS (apci) m/z=493.1(M+H).

Example 324

(R)-2-(4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-1-phenylethanol

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(22.1 mg, 0.0615 mmol) and (R)-(+)-Styrene oxide (8.43 μL, 0.0738 mmol)in methanol (1.2 mL) was heated at 75° C. in a sealed tube overnight.The reaction mixture was subsequently cooled to ambient temperature anddirectly purified by silica chromatography (10-90% DCM/acetone) toafford the title compound (7.8 mg, 27% yield). MS (apci) m/z=480.1(M+H).

Example 325

tert-butyl4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube, a solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P8; 150 mg, 0.394 mmol) indioxane (3 mL) was treated with tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(230 mg, 0.591 mmol), 2 M Na₂CO_(3(aq)) (985 μL, 1.97 mmol) andPd(PPh₃)₄ (22.8 mg, 0.0197 mmol). The reaction mixture was purged withnitrogen, sealed and heated at 90° C. overnight. After cooling toambient temperature, the reaction mixture was diluted with H₂O (10 mL)and extracted with DCM (3×15 mL). The combined organic extracts weredried over anhydrous MgSO₄, vacuum filtered, and concentrated in vacuo.The crude residue was purified by silica chromatography (25-100%EtOAc/hexanes) to afford the title compound as a solid contaminated withtriphenylphosphine oxide (131 mg). That solid mixture was suspended inMTBE (3 mL), sonicated then vacuum filtered to cleanly provide the titlecompound (75.7 mg, 39% yield). MS (apci) m/z=494.0 (M+H).

Example 326

3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride

Tert-butyl4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(70 mg, 0.14 mmol) was suspended in EtOH (0.5 mL) and DCM (0.5 mL) andthen treated with 5 M HCl in iPrOH (0.5 mL, 2.8 mmol). The reactionmixture was stirred at ambient temperature overnight. The resultingsuspension was concentrated in vacuo. The solids were sonicated in Et₂Oand then dried in vacuo to cleanly afford the title compound (75 mg,quantitative yield). MS (apci) m/z=394.0 (M+H).

Example 327

(R)-1-(4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-hydroxy-2-phenylethanone

A solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (8.0 mg, 0.017 mmol) in DCM (0.5 mL) was treated withD-(−)-Mandelic acid (3.13 mg, 0.0206 mmol), HATU (7.82 mg, 0.0206 mmol)and DIEA (29.85 μL, 0.1714 mmol). The resulting reaction mixture wasstirred at ambient temperature overnight and then directly purified bysilica chromatography (5-60% DCM/acetone) to afford the title compound(3.9 mg, 43% yield). MS (apci) m/z=528.1 (M+H).

Example 328

1-(4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethanone

A solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (10 mg, 0.021 mmol) and 2-(dimethylamino)acetyl chloridehydrochloride (5.1 mg, 0.032 mmol) in DCM (0.4 mL) was treated with DIEA(22 μL, 0.13 mmol) and the reaction mixture was stirred at ambienttemperature overnight. The reaction was quenched with the addition ofMeOH (0.2 mL), partially concentrated in vacuo and then purified byreverse phase chromatography (5-75% ACN/water) to afford the titlecompound (6.2 mg, 60% yield). MS (apci) m/z=479.0 (M+H).

Example 329

1-(4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-methoxyethanone

A solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (10 mg, 0.021 mmol) in DCM (0.4 mL) was treated with a10 M solution of 2-methoxyacetyl chloride in DCM (2.9 μL, 0.032 mmol)and DIEA (19 μL, 0.11 mmol) and the reaction mixture was stirred atambient temperature overnight. The reaction was quenched with theaddition of MeOH (0.2 mL). The resulting suspension was sonicated andvacuum filtered, rinsing the solids collected with Et₂O (2×1 mL), toafford the title compound (7.2 mg, 72% yield). MS (apci) m/z=466.0(M+H).

The compounds in Table CC were prepared and purified according themethod described for the synthesis of Example 329, replacing2-methoxyacetyl chloride for the appropriate acid chloride startingmaterial. Sonication was performed using either MeOH or Et₂O.

TABLE CC MS (apci) Ex# Structure Chemical Name m/z 330

1-(4-(5-(3-chloro-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)piperazin-1- yl)ethanone 436.1 (M + H) 331

1-(4-(5-(3-chloro-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin- 2-yl)piperazin-1-yl)-3,3- dimethylbutan-1-one492.1 (M + H)

Example 332

3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

A solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinehydrochloride (8.9 mg, 0.021 mmol) in DCM (1 mL) was treated pyridine(8.4 μL, 0.10 mmol) and methanesulfonic anhydride (4.3 mg, 0.025 mmol)and the reaction mixture was stirred at ambient temperature for 6 d.Additional pyridine (0.1 mL, 1.19 mmol) and methanesulfonic anhydride(20 mg, 0.115 mmol) were added and the reaction mixture was stirred foran additional 18 h. The crude reaction mixture was purified by silicachromatography (25-100% EtOAc/hexanes) to cleanly provide the titlecompound (1.5 mg, 15% yield). MS (apci) m/z=472.0 (M+H).

Example 333

3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

In a pressure tube, a solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P8; 15 mg, 0.039 mmol) indioxane (0.5 mL) was treated with(6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid (13 mg, 0.059mmol), 2 M Na₂CO_(3(aq)) (98 μL, 0.20 mmol) and Pd(PPh₃)₄ (2.3 mg,0.0020 mmol). The reaction mixture was purged with nitrogen, sealed andthen heated at 90° C. overnight. After cooling to ambient temperature,the reaction mixture was diluted with water (25 mL) and extracted withDCM (25 mL) and then with a 5:95 solution of MeOH/DCM (2×25 mL). Thecombined organic extracts were dried over anhydrous MgSO₄, vacuumfiltered, and concentrated in vacuo. The crude residue was purifieddirectly by reverse phase chromatography (5-60% ACN/water) to afford thetitle compound as a solid contaminated with triphenylphosphine oxide(9.0 mg). That material was purified by preparative thin layer silicachromatography (10:90 0.2 M NH₃ in MeOH:DCM). The lower band wasisolated, suspended in 10:90 MeOH/DCM with NH₄OH, and then filtered. Thefiltrate was concentrated in vacuo to cleanly provide the title compound(7.1 mg, 44% yield). MS (apci) m/z=408.1 (M+H).

Example 333a

3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride

In a pressure tube a solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P8; 95 mg, 0.250 mmol) indioxane (3 mL) was treated with(6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid (82.7 mg, 0.374mmol), 2 M Na₂CO_(3(aq)) (624 μL, 1.25 mmol) and Pd(PPh₃)₄ (14.4 mg,0.0125 mmol). The reaction mixture was purged with nitrogen, sealed andthen heated at 90° C. overnight. After cooling to ambient temperature,the reaction mixture was diluted with water (25 mL) and extracted with a10:90 solution of MeOH/DCM (3×25 mL). The combined organic extracts weredried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (5-60%ACN/water with 0.1 N HCl). The product was triturated in Et₂O (5 mL) andthen filtered. The isolated solids were rinsed with Et₂O (3 mL) anddried in vacuo to afford the title compound (69.3 mg, 58% yield). MS(apci) m/z=408.0 (M+H).

Example 334

tert-butyl8-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

In a pressure tube a solution of3-chloro-4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(Intermediate P9; 8 mg, 0.024 mmol) and tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride (52 mg, 0.24mmol) in DMSO (3 mL) was heated at 150° C. for 2 d. The reaction mixturewas cooled to ambient temperature and then directly purified by reversephase chromatography (5-95% ACN/water) to afford the title compound (8.0mg, 63% yield). MS (apci) m/z=520.2 (M+H).

Example 335

4-(6-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridinedihydrochloride

A mixture of t-Butyl8-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(Example 334, 7.3 mg, 0.0140 mmol) in 5 M HCl in iPrOH (562 μL, 2.81mmol) was stirred at ambient temperature for 1 h and then concentratedin vacuo to afford the title compound (6.2 mg, 90% yield). MS (apci)m/z=420.1 (M+H).

Example 336

1-(8-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(dimethylamino)ethanone

A solution of4-(6-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridinedihydrochloride (5 mg, 0.010 mmol) and 2-(dimethylamino)acetyl chloridehydrochloride (2.4 mg, 0.015 mmol) in DCM (0.4 mL) was treated with DIEA(11 μL, 0.061 mmol) and the resulting solution was stirred at ambienttemperature overnight. The reaction was quenched with the addition ofMeOH (0.2 mL), concentrated in vacuo and purified by reverse phasechromatography (5-75% ACN/water) to afford the title compound (2.1 mg,12% yield). MS (apci) m/z=505.1 (M+H).

Example 337

tert-butyl3-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

In a microwave vial a solution of3-chloro-4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(Intermediate P9; 5 mg, 0.015 mmol) and tert-butyl3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (9.1 mg, 0.046 mmol) inDMSO (0.2 mL) was subjected to microwave irradiation at 130° C. for 5 hand then at 150° C. for 6 h. The reaction mixture was cooled to ambienttemperature and then directly purified by reverse phase chromatography(5-95% ACN/water) to afford the title compound (2.6 mg, 34% yield). ¹HNMR (CDCl₃) δ 8.51 (d, 1H), 8.34 (d, 1H), 7.88 (s, 1H), 7.76 (s, 1H),7.65 (m, 2H), 7.12 (d, 1H), 6.62 (d, 1H), 4.33 (m, 2H), 4.20 (m, 2H),3.98 (s, 3H), 3.55 (m, 2H), 1.45 (d, 2H), 1.38 (s, 9H).

Example 338

3-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptanedihydrochloride

A mixture of t-Butyl3-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate(Example 337, 1.24 mg, 0.00245 mmol) in 5 M HCl in iPrOH (98.0 μL, 0.490mmol) was stirred at ambient temperature for 1 h and then concentratedin vacuo to afford the title compound (0.98 mg, 84% yield). MS (apci)m/z=406.0 (M+H).

Example 339

3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

In a pressure tube a solution of3-chloro-4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(Intermediate P9; 16 mg, 0.0488 mmol) and pyrrolidine (40.8 μL, 0.488mmol) in DMA (0.5 mL) was heated at 110° C. overnight. The reactionmixture was cooled to ambient temperature and then directly purified byreverse phase chromatography (5-95% ACN/water containing 0.1% TFA) toafford the title compound as a TFA salt (27 mg) which was subsequentlydissolved in MeOH and filtered through a basic resin (Stratospheres SPEHCO3-MP resin, 100 mg, 0.18 mmol/g). The filtrate was concentrated invacuo to afford the title compound (13.3 mg, 72% yield). MS (apci)m/z=379.0 (M+H).

Example 340

4-(6-(7-azabicyclo[2.2.1]heptan-7-yl)pyridin-3-yl)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

In a pressure tube a solution of3-chloro-4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine(Intermediate P9; 10 mg, 0.031 mmol) and 7-azabicyclo[2.2.1]heptanehydrochloride (12 mg, 0.092 mmol) in DMA (0.3 mL) was heated at 110° C.overnight. Additional 7-azabicyclo[2.2.1]heptane hydrochloride (12 mg,0.092 mmol) was added along with DIEA (18 μL, 0.15 mmol). The reactionmixture was heated at 110° C. for 7 d and then cooled to ambienttemperature. The reaction mixture was diluted with EtOAc (25 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover anhydrous MgSO₄, filtered, concentrated and purified by reversephase chromatography (5-95% ACN/water) to afford the title compound (10mg, 37% yield). MS (apci) m/z=405.0 (M+H).

Example 341

4-(6-(4-(1-(4-chlorophenyl)cyclopropanecarbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

1-(4-chlorophenyl)cyclopropanecarboxylic acid (12.9 mg, 0.0656 mmol) andHATU (24.9 mg, 0.0656 mmol) were dissolved in DMA (273 μL) at roomtemperature. After 25 min,6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitriledihydrochloride (Example 2; 25 mg, 0.0547 mmol) and DIEA (47.6 μL, 0.273mmol) were added sequentially. The reaction mixture was stirred 18 h atroom temperature and then directly purified by C18 reverse phasechromatography (5-85% ACN/water as the gradient eluent) to provide thetitle compound (22.6 mg, 71% yield). MS (apci) m/z=563.3 (M+H).

The compounds in the Table FF were prepared according to the methoddescribed for Example 341, replacing1-(4-chlorophenyl)cyclopropanecarboxylic acid with the appropriatecarboxylic acid starting material. Reaction progression in each wasfollowed by LCMS, and reaction times were adjusted as necessary.Products were purified as in Example 341 (except where noted), utilizingthe appropriate gradient eluent in chromatography to cleanly afford thetitle compounds.

TABLE FF MS (apci) Ex # Structure Chemical Name m/z 342*

6-(1-methyl-1H- pyrazol-4-yl)-4- (6-(4-(4- phenyltetrahydro- 2H-pyran-4-carbonyl)piperazin- 1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 573.3 (M + H) 343

4-(6-(4-(1-(2,4- dichlorophenyl)cyclo- propanecarbon- yl)piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 597.1 (M + H) 344

4-(6-(4-(1-(4- methoxyphenyl)cyclo- propanecarbonyl) piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 559.2 (M + H) 345

4-(6-(4-(1-(4- fluorophenyl)cyclo- propanecarbonyl) piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 547.2 (M + H) 346

6-(1-methyl-1H- pyrazol-4-yl)-4- (6-(4-(1- (trifluoromethyl)cyclo-propanecarbonyl) piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 521.3 (M + H) 347

4-(6-(4-(1- (hydroxymethyl)cyclo- propanecarbonyl) piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 483.3 (M + H) 348

4-(6-(4-(1- cyanocyclopropane- carbonyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 478.3 (M + H) 349

4-(6-(4-(1-(3- fluorophenyl)cyclo- propanecarbonyl) piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 547.2 (M + H) 350

6-(1-methyl-1H- pyrazol-4-yl)-4- (6-(4-(1-(pyrazin- 2- yl)cyclopropane-carbonyl)piperazin- 1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 531.2 (M + H) 351

4-(6-(4-(2- (dimethylamino)- 2-(4-fluoro- phenyl)acetyl) piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 564.2 (M + H) 352

4-(6-(4-(3- methoxy-2,2- dimethylpropanoyl) piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 499.2 (M + H) 353

4-(6-(4-(1- (methoxymethyl) cyclopropanecarb- onyl)piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 497.2 (M + H) 354

4-(6-(4-(1- (methoxymethyl) cyclobutanecarbo- nyl)piperazin-1-yl)pyridin-3-yl)- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 511.2 (M + H) *Example 342: Instead ofdirectly chromatographing the reaction mixture, it was triturated withEtOAc and the title compound was isolated by filtration, rinsing solidswith EtOAc and Et₂O and drying in vacuo.

The compounds in Table GG were prepared according the method describedfor the synthesis of Example 33, replacing 3-(dimethylamino)propanoicacid with the appropriate carboxylic acid starting material. Reactionswere monitored by LCMS, and reaction times were adjusted as necessary.Products were purified by reverse-phase preparative HPLC utilizing anappropriate gradient eluent with 0.1 v/v % TFA to cleanly afford thetitle compounds as TFA salts.

TABLE GG MS (apci) Ex # Structure Chemical Name m/z 355

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(piperidine-2-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 496.2 (M + H) 356

4-(6-(4-(1-(3- chlorophenyl)cyclopropane- 1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate 563.1 (M + H) 357

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2-(4- (trifluoromethoxy)phenyl)acetyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate 587.2 (M + H) 358

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2- morpholinobenzoyl)pipera-zin-1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) 574.2 (M + H) 359

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(1-(pyridine- 2-yl)cyclopropane-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 530.2 (M + H) 360

4-(6-(4-(2-(5- fluoropyridin-2- yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 522.2 (M + H) 361

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2-(4- methylpiperazin-1-yl)acetyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile tris(2,2,2-trifluoroacetate) 525.2 (M + H) 362

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2- morpholinoacetyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) 512.2 (M + H) 363

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2- morpholino-2-phenylacetyl)piperazin-1- y)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 588.2 (M + H) 364

4-(6-(4-(2-(diethylamino)- 2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 574.3 (M + H) 365

4-(6-(4-(2-(4-cyano- phenyl)acetyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 528.2 (M + H) 366

4-(6-(4-(1-(2- methoxyethyl)-1H- pyrazole-3- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 537.2 (M + H) 367

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(3-methyl-5- propylisoxazole-4-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate 536.2 (M + H) 368

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(2-phenyl-2- (piperidin-1-yl)acetyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 586.3 (M + H) 369

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4-(1-(pyridine- 3-yl)cyclopropane-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 530.2 (M + H) 370

4-(6-(4-(5-cyclopropyl- 1H-pyrazole-3- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile bis(2,2,2-trifluoroacetate) 519.2 (M + H)

Example 371

(S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 15 mg 0.033 mmol) in DMF (0.2 mL) wastreated with TEA (14 μL, 0.098 mmol) and(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (12 mg, 0.049mmol). The reaction mixture was stirred for 1 h at room temperature andthen purified directly by C18 reverse phase chromatography (0-60%ACN/water as the gradient eluent) to afford the title compound (13 mg,66% yield). MS (apci) m/z=601.1 (M+H).

Example 372

(R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Using the procedure outlined for Example 371, replacing(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride with(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride, the titlecompound was cleanly isolated (16 mg, 61% yield) after purification byC18 reverse phase chromatography (0-60% ACN/water as the gradienteluent). MS (apci) m/z=601.2 (M+H).

Example 373

(R)-4-(6-(4-(3-hydroxy-2-phenylpropanol)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 50.3 mg, 0.110 mmol) in DCM (1.10 mL) wastreated with (R)-3-hydroxy-2-phenylpropanoic acid (Intermediate R12;21.9 mg, 0.132 mmol), HATU (50.2 mg, 0.132 mmol) and DIEA (191.6 μL,1.10 mmol). The reaction was stirred overnight at room temperature, andthen directly purified by silica chromatography (10-90% DCM/Acetone) toafford the title compound (32.0 mg, 55% yield). MS (apci) m/z=533.2(M+H).

Example 374

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((1-methylcyclopropyl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 25 mg, 0.055 mmol),1-methylcyclopropane-1-sulfonyl chloride (8.45 mg, 0.0547 mmol) and TEA(76 μL, 0.55 mmol) in DMA (500 μL) was stirred 20 h at 70° C. The crudereaction mixture was purified directly by silica chromatography (0.2%MeOH/0.2% NH₄OH in DCM) to afford the title compound (8.5 mg, 31%yield). MS (apci) m/z=503.2 (M+H).

Example 375

(S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(3-phenylpyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitriledihydrochloride (Example 2; 25 mg, 0.055 mmol) and DIEA (57 μL, 0.33)mmol) in DriSolv® DCM (164 μL) was added dropwise to a 0° C. solution oftriphosgene (8.1 mg, 0.027 mmol) in DriSolv® DCM (273 μL). Afterstirring for 90 min at 0° C., the reaction mixture was treated with(S)-3-phenylpyrrolidine hydrochloride (15 mg, 0.082 mmol), then stirredfor 48 h at room temperature. The resulting mixture was purifieddirectly by C18 reverse-phase chromatography (5-75% ACN/water as thegradient eluent) to provide the title compound (9.5 mg, 31% yield). MS(apci) m/z=558.2 (M+H).

The compounds in Table HH were prepared according to the methoddescribed for the synthesis of Example 375, replacing(S)-3-phenylpyrrolidine hydrochloride with the appropriate aminestarting material. Reactions were monitored by LCMS and reaction timeswere adjusted as necessary. Products were purified by C18 reverse-phasechromatography utilizing an appropriate gradient eluent to cleanlyafford the title compound.

TABLE HH MS (apci) Ex # Structure Chemical Name m/z 376

4-(6-(4-(4- methoxypiperidine-1- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 526.2 (M + H) 377

N-butyl-4-(5-(3-cyano- 6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine- 2-yl)-N- phenylpiperazine-1- carboxamide 560.1(M + H) 378

(R)-6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(4- (3-phenylpyrrolidine-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 558.2 (M + H) 379

6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(4- (3- morpholinopyrrolidine-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 567.2 (M + H) 380

4-(6-(4-(3- azabicyclo[3.1.0]hexane- 3-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 494.1 (M + H) 381

6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(4- (octahydropyrrolo[1,2-a]pyrazine-2- carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 537.3 (M + H) 382

4-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine- 2-yl)-N-(2- methoxyphenyl)-N-methylpiperazine-1- carboxamide 548.3 (M + H) 383

4-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin- 2-yl)-N-(4- methoxyphenyl)-N-methylpiperazine-1- carboxamide 548.3 (M + H) 384

4-(6-(4-(6,6-dimethyl- 3- azabicyclo[3.1.0]hexane- 3-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 522.4 (M + H) 385

4-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine- 2-yl)-N,N-bis(2- methoxyethyl)piperazine-1-carboxamide 544.2 (M + H)

The compounds in Table II were prepared according the method describedfor the synthesis of Example 130, replacing2-methoxy-N-methyl-ethanamine with the appropriate amine startingmaterial. Reactions were monitored by LCMS, and reaction times wereadjusted as necessary. Products were purified by reverse-phasepreparative HPLC utilizing an appropriate gradient eluent to cleanlyafford the title compounds.

TABLE II MS (apci) Ex # Structure Chemical Name m/z 386

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-2-yl)-N- cyclopropyl-N- methylpiperazine-1- carboxamide2,2,2- trifluoroacetate 482.2 (M + H) 387

4-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N- methylpiperazine-1- carboxamide 442.1 (M + H)

Example 388

4-(6-(4-(3-cyclopropylpyrrolidine-1-carbnyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of 4-nitrophenyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A room temperature suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 100 mg, 0.219 mmol) in DMA (2 mL) wastreated sequentially with DIEA (114 μL, 0.656 mmol) and 4-nitrophenylcarbonochloridate (66.1 mg, 0.328 mmol). The mixture was stirred at roomtemperature for 4 h, at which point LCMS indicated that the titlecompound had formed as the major product, MS (apci) m/z=550 (M+H). Thereaction mixture was divided into 6 equal fractions, and one fractionwas used directly in Step 2. The remaining five parts were reserved, andused in the preparation of each of the compounds listed in Table JJ.

Step 2: Preparation of4-(6-(4-(3-cyclopropylpyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of 3-cyclopropylpyrrolidine (6.1 mg, 0.055mmol) in DMA (0.1 mL) and DIEA (19 μL, 0.11 mmol) was treated with asuspension of 4-nitrophenyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)piperazine-1-carboxylate(⅙th of the suspension from Step 1; about 20 mg, 0.036 mmol) in DIEA/DMA(about 0.35 mL, about 0.33 M). The resulting mixture was stirred for 16h at 80° C. The reaction mixture was cooled to room temperature, dilutedwith water (1 mL), and then filtered. The solid filter cake was rinsedwith water, then dissolved in ACN and purified by C18 reverse-phasechromatography (5-90% ACN/water as the gradient eluent) to cleanlyafford the title compound (5.6 mg, 29% yield). MS (apci) m/z=522.2(M+H).

The compounds in Table JJ were prepared according the method describedin Step 2 in the synthesis of Example 388, replacing3-cyclopropylpyrrolidine with the appropriate amine starting material.Reactions were monitored by LCMS, and reaction times were adjusted asnecessary. Compounds were purified by C18 reverse-phase chromatographyutilizing an appropriate gradient eluent to cleanly afford the titlecompound.

TABLE JJ MS (apci) Ex # Structure Chemical Name m/z 389

4-(6-(4-(3- ethylpyrrolidine-1- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 510.2 (M + H) 390

4-(6-(4-(3- isopropylpyrrolidine-1- carbonyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 524.2 (M + H) 391

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(3- (trifluoromethyl)pyrrolidine-1-carbonyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 550.2 (M + H)

Example 392

4-(6-(4-(2-isopropoxyethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.018 g, 0.0394 mmol) in dry DMF (0.3 mL)and TEA (54.9 μL, 0.394 mmol) was treated with 2-(2-bromoethoxy)propane(0.0197 g, 0.118 mmol). The reaction mixture was stirred overnight at75° C., and then additional 2-(2-bromoethoxy)propane (1 eq) and TEA (1eq) were added. The reaction mixture was allowed to stir 24 h at 75° C.After cooling to room temperature, the resulting reaction mixture wasdirectly purified by C18 reverse phase chromatography (5-99% ACN/wateras the gradient eluent) to afford the title compound (7.4 mg, 41%yield). MS (apci) m/z=471.2 (M+H).

The compounds in Table KK were prepared according to the methoddescribed for the synthesis of Example 392, using either DMF or DMA asthe reaction solvent, and replacing 2-(2-bromoethoxy)propane with theappropriate alkyl halide starting materials. Reactions were monitored byLCMS, and reaction times/temperatures were adjusted accordingly. In somecases, the addition of extra equivalents of alkyl halide/TEA (1-5 eq)after 24 h at 75° C. was required. Title compounds were cleanly isolatedfollowing C18 reverse phase chromatography utilizing an appropriategradient eluent.

TABLE KK MS (apci) Ex # Structure Chemical Name m/z 393

4-(6-(4-isobutylpiperazin- 1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 441.1 (M + H) 394

4-(6-(4-(cyclo- propylmethyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 439.2(M + H) 395

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(2-(pyridine-2-yl)ethyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 490.2 (M + H) 396

4-(6-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 443.2(M + H) 397

4-(6-(4-(2- ethoxyethyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 469.2(M + H) 398

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(2-(trifluoro-methoxy)ethyl)piperazin- 1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 497.1 (M + H) 399

4-(6-(4-((6- methoxypyridin-2- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 506.2 (M + H) 400

4-(6-(4-((2- methoxypyridin-4- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 506.2 (M + H) 401*

4-(6-(4-((4,6- dimethylpyrimidin-2- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 505.2 (M + H) *Example 401: used only 1.5 eq of the akylhalide (2-(chloromethyl)-4,6-dimethylpyrimidine), 10 eq of TEA, and wasconducted at room temperature, but otherwose followed a similarprocedure.

Example 402

4-(6-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.0199 g, 0.0435 mmol) in dry DMF (1 mL) wastreated with Cs₂CO₃ (0.0425 g, 0.131 mmol) and4-bromotetrahydro-2H-thiopyran-1,1-dioxide (0.0185 g, 0.0870 mmol). Theresulting mixture was stirred for 4 h at 60° C., then overnight at 75°C., and then additional 4-bromotetrahydro-2H-thiopyran 1,1-dioxide (20mg, 0.939 mmol) and Cs₂CO₃ (40 mg, 0.301 mmol) were added. After 3 d at75° C., this process was repeated, adding4-bromotetrahydro-2H-thiopyran-1,1-dioxide (35 mg, 0.164 mmol) andCs₂CO₃ (60 mg, 0.451 mmol), then stirring for an additional 24 h at 75°C. The reaction mixture was purified directly by C18 reverse phasechromatography (5-99% ACN/Water as the gradient eluent) to afford thetitle compound (4.2 mg, 19% yield). MS (apci) m/z=562.1 (M+2 Na).

Example 403

4-(6-(4-(2-(isopropylsulfonyl)ethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 25 mg, 0.055 mmol),2-((2-chloroethyl)sulfonyl)propane (18.7 mg, 0.109 mmol) and TEA (76 μL,0.55 mmol) in dry DMA (500 μL) was stirred for 3 d at 70° C. Thereaction mixture was purified directly by silica chromatography (2%MeOH! 0.02% NH₄OH in DCM as the eluent) to afford the title compound(8.6 mg, 30% yield). MS (apci) m/z=519.2 (M+H).

The compounds in Table LL were prepared according to the methoddescribed for the synthesis of Example 403, replacing2-((2-chloroethyl)sulfonyl)propane with the appropriate alkyl halide.Reactions were monitored for completion by LCMS, and reaction times wereadjusted accordingly. Title compounds were cleanly isolated followingsilica chromatography (2% MeOH!0.02% NH₄OH in DCM as the eluent) unlessotherwise noted.

TABLE LL MS (apci) Ex # Structure Chemical Name m/z 404*

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((tetrahydro- 2H-pyran-2-yl)methyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 483.3 (M + H) 405**

4-(6-(4-(3- methoxypropyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 457.2(M + H) 406

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4- ((tetrahydrofuran-3-yl)methyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 469.2 (M + H) *isolated following in vacuo removal of DMAfollowed by trituration with EtOAc and filtration **4 eq of the alkylhalide was used

Example 407

4-(6-(4-(2-cyclopropoxyethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitriledihydrochloride (Example 2; 0.0185 g, 0.0404 mmol) in dry DMF (0.3 mL)was treated with TEA (56.3 μL, 0.404 mmol) and(2-chloroethoxy)cyclopropane (0.0146 g, 0.121 mmol). The reactionmixture was stirred overnight at 75° C., and then additional(2-chloroethoxy)cyclopropane (1 eq) and DMF (0.2 mL) with KI (20.1 mg,0.121 mmol) were added. The reaction was allowed stir for 48 h at 75°C., then cooled to room temperature. The reaction mixture was purifieddirectly by C18 reverse phase chromatography (5-80% ACN/water as thegradient eluent) to afford the title compound (4.4 mg, 23% yield). MS(apci) m/z=469.2 (M+H).

Example 408

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-propylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitriledihydrochloride (Example 2; 20 mg, 0.044 mmol) in DMF (300 μL) and TEA(61 μL, 0.44 mmol) was treated with 1-iodopropane (8.5 μL, 0.087 mmol).The reaction mixture was stirred overnight at room temperature, and thenadditional 1-iodopropane (8.5 μL, 0.087 mmol; 1 eq) was added. Thereaction was allowed to stir at room temperature until complete by HPLC.The reaction mixture was directly purified by C18 reverse phasechromatography (10-99% ACN/Water as the gradient eluent) to afford thetitle compound (12 mg, 64% yield). MS (apci) m/z=427.2 (M+H).

The compounds in Table MM were prepared according to the methoddescribed for the synthesis of Example 408 (except where noted),replacing 1-iodopropane with the appropriate alkyl halide starting.Reactions were monitored by HPLC, and reaction times adjustedaccordingly. In some cases, additional alkyl halide (1 eq)/TEA (1.2 eq)was required after stirring overnight. Title compounds were cleanlyisolated following C18 reverse phase chromatography utilizing anappropriate gradient eluent.

TABLE MM MS (apci) Ex # Structure Chemical Name m/z 409

4-(6-(4-ethylpiperazin-1- yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 413.2 (M + H) 410

4-(6-(4-isopropylpiperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 427.2(M + H) 411*

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4- phenethylpiperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 489.2 (M + H)*reaction was conducted at 75° C.

Example 412

(R)-4-(6-(4-(2-methoxypropyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

NaH (60% w/w dispersion in mineral oil; 1.12 mg, 0.0280 mmol) was addedto a cold (0° C.) solution of(R)-4-(6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 158; 6.2 mg, 0.0140 mmol) in dry THF (0.2 mL), and the reactionmixture was stirred for 10 min at 0° C. CH₃I (1 M in THF; 1.74 μL,0.0280 mmol) was added to the 0° C. mixture. The reaction mixture wasstirred at room temperature at 0° C. overnight. The reaction wasquenched with water and CHCl₃. The biphasic mixture was separated, theaqueous phase was extracted with CHCl₃, and the combined organicextracts were filtered through a PS frit. The filtrate was concentratedin vacuo, and the residue was purified by C18 reverse phasechromatography (25-90% ACN/water as the gradient eluent) to afford thetitle compound (2.8 mg, 44% yield). MS (apci) m/z=457.1 (M+H).

The compounds in Table NN were prepared according to the methoddescribed for the synthesis of Example 412, replacing(R)-4-(6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 158) with the appropriate alcohol. Reactions were monitored forcompletion by LCMS, and reaction times were adjusted accordingly. Thetitle compounds were cleanly isolated following C18 reverse phasechromatography using an appropriate gradient.

TABLE NN MS (apci) Ex # Structure Chemical Name m/z 413*

4-(6-(4-(2-methoxy-3- methylbutyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 485.2(M + H) 414

4-(6-(4-(2-methoxy-2- methylpropyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 471.2(M + H) 415

(S)-4-(6-(4-(2- methoxypropyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 457.1(M + H) 416

4-(6-(4-((3r,4s)-4- methoxytetrahydrofuran-3- yl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 485.2 (M + H) 417

4-(6-(4-(2-methoxy-3,3- dimethylbutyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 499.3 (M + H) *Example 413 utilized DCM inquench/work-up.

Example 418

4-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.0199 g, 0.0435 mmol) in DMF (0.3 mL) wastreated with TEA (60.6 μL, 0.435 mmol) and 2,2-difluoroethyltrifluoromethanesulfonate (0.0279 g, 0.131 mmol). The reaction mixturewas stirred overnight at 65° C., and then purified directly by C18reverse phase chromatography (5-99% ACN/water as the gradient eluent) toafford the title compound (10.6 mg, 54% yield). MS (apci) m/z=449.2(M+H).

Example 419

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.0203 g, 0.0444 mmol) in dry DMF (0.3 mL)was treated with TEA (61.9 μL, 0.444 mmol) and1,1,1-trifluoro-2-iodoethane (0.0280 g, 0.133 mmol). The resultingsuspension was stirred overnight at 70° C., and then additional dry DMF(0.2 mL), TEA (50 μL, 0.359 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (19.8 μL, 0.133 mmol) were added. Theresulting solution was stirred for 3 d at 70° C. After cooling to roomtemperature, the reaction mixture was purified directly by C18 reversephase chromatography (5-99% ACN/water as the gradient eluent) to affordthe title compound (12.8 mg, 62% yield). MS (apci) m/z=467.1 (M+H).

Example 420

4-(6-(4-(2-(tert-butoxy)ethyl)piperazin-1-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitriledihydrochloride (Example 2; 0.0175 g, 0.0383 mmol) in dry DMF (0.3 mL)was treated with TEA (53.3 μL, 0.383 mmol) and 2-(tert-butoxy)ethylmethanesulfonate (0.0150 g, 0.0765 mmol). The reaction mixture wasstirred overnight at 75° C., and then additional 2-(tert-butoxy)ethylmethanesulfonate (7.5 mg, 0.0.0383 mmol) and dry DMF (0.2 mL) wereadded. The reaction was allowed to stir 48 h at 75° C., then for 24 h at85° C. The reaction mixture was cooled to room temperature and purifieddirectly by C18 reverse phase chromatography (20-90% ACN/water as thegradient eluent) to afford the title compound (8.7 mg, 47% yield). MS(apci) m/z=485.2 (M+H)

Example 421

(R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(1-phenylethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride Step 1: Preparation of (S)-1-phenylethylmethanesulfonate

A cold (0° C.) solution of (S)-1-phenylethanol (0.95 g, 7.78 mmol) andTEA (2.17 mL, 15.6 mmol) in DCM (10 mL) was treated over a 20 min periodwith methanesulfonyl chloride (1.07 g, 9.33 mmol). The resultingreaction mixture was allowed to warm to room temperature. The roomtemperature mixture was quenched with water (2 mL), and the combinedorganic extracts were separated using phase separation chromatographyand concentrated in vacuo. The resultant oil was used directly in Step2.

Step 2: Preparation of(R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(1-phenylethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.05303 g, 0.1159 mmol) in dry DMF (0.9 mL)was treated with Cs₂CO₃ (0.3778 g, 1.159 mmol) and (S)-1-phenylethylmethanesulfonate (0.1393 g, 0.3478 mmol). The resulting mixture wasstirred overnight at 70° C., and then additional (S)-1-phenylethylmethanesulfonate (50 μL) was added. The reaction temperature was raisedto 80° C., and the reaction was allowed to stir for an additional 24 h.The reaction mixture was quenched with water/DCM. The combined organicextracts were separated, filtered through PS paper, and concentrated invacuo. The residue was purified by C18 reverse phase chromatography(10-99%, ACN/Water with 0.01% HCl as the gradient eluent) to afford thetitle compound as the di-HCl salt (11.2 mg, 20% yield). MS (apci)m/z=489.2 (M+H).

Example 422

(S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(1-phenylethyl)piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

The title compound was prepared according to the method described forthe synthesis of Example 421, replacing (S)-1-phenylethanol with(R)-1-phenylethanol in Step 1, and replacing (S)-1-phenylethylmethanesulfonate with (R)-1-phenylethyl methanesulfonate in Step 2, andincreasing amounts of both the methanesulfonate reagent (6 eq) andCs₂CO₃ (13 eq). Following C18 reverse phase chromatography (10-99%,ACN/Water with 0.01% HCl as the gradient eluent) the title compound wascleanly isolated as the di-HCl salt (13.7 mg, 25% yield). MS (apci)m/z=489.2 (M+H).

Example 423

4-(6-(4-((5-fluoropyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 30.00 mg, 78.04 mmol) and5-fluoronicotinaldehyde (14.64 mg, 117.06 mmol) in DMF (1.00 mL) wastreated with TEA (32.45 mL, 234.12 mmol). The mixture was acidified topH 6 with acetic acid, and then stirred for 2 h at 25° C. NaBH₃CN (9.808mg, 156.08 mmol) was added to the reaction mixture. The resultingmixture was stirred at 25° C. for 10 h. The reaction mixture wasfiltered to remove particulates, and the filtrate was purified bypreparative HPLC (10 mM NH₄(HCO3)/ACN) to afford the title compound(14.8 mg, 38% yield). MS (apci) m/z=494.1 (M+H), 516.1 (M+Na).

The compounds in Table 00 were prepared according to the methoddescribed for the synthesis of Example 423, replacing5-fluoronicotinaldehyde with the appropriate aldehyde. Reactions weremonitored for completion by LCMS, and reaction times were adjustedaccordingly. Title compounds were cleanly isolated following preparativeHPLC using an appropriate gradient eluent.

TABLE OO MS (apci) Ex # Structure Chemical Name m/z 424

4-(6-(4-(4- fluorobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 493.1(M + H) 425

4-(6-(4-(4- chlorobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 509.1(M + H) 426

4-(6-(4-(2,4- difluorobenzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 511.1(M + H) 427

4-(6-(4-(2- fluorobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 493.2(M + H) 428

4-(6-(4-(3- fluorobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 493.1(M + H) 429

4-(6-(4-(2,5- difluorobenzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 511.2(M + H) 430

4-(6-(4-((5-chloropyridin- 3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 510.1 (M + H) 431

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((6- methylpyrazin-2-yl)methyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 491.2 (M + H) 432

4-(6-(4-(4- methoxybenzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 505.2(M + H) 433

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((6- methylpyridin-2-yl)methyl)piperazin-1- yl)pyridine-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 490.2 (M + H) 434

4-(6-(4-((3-fluoropyridin- 4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 494.2 (M + H) 435

4-(6-(4-((1,5-dimethyl-1H- pyrazol-4- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 493.2 (M + H) 436

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((5- methylisoxazol-3-yl)methyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 480.1 (M + H) 437

4-(6-(4-((1-methyl-1H- imidazol-2- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 479.2 (M + H) 438

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((3- methylpyridin-2-yl)methyl)piperazin-1- yl)pyridine-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 490.2 (M + H) 439

4-(6-(4-((1-methyl-1H- pyrazol-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 479.2 (M + H) 440

4-(6-(4-((1,3-dimethyl-1H- pyrazol-4- yl)methyl)piperazin-1-yl)pyridine-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 493.2 (M + H) 441

4-(6-(4-(2,6- difluorobenzyl)piperazin- 1-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 511.1(M + H) 442

4-(6-(4-((5- methoxypyridin-3- yl)methyl)piperazin-1-yl)pyridine-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 506.2 (M + H) 443

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((4- methylpyridin-2-yl)methyl)piperazin-1- yl)pyridine-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 490.2 (M + H) 444

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((5- methylpyrazin-2-yl)methyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 491.1 (M + H) 445

4-(6-(4-((1-isopropyl-1H- pyrazol-4- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 507.2 (M + H) 446

4-(6-(4-((1-ethyl-1H- pyrazol-4- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 493.2 (M + H) 447

4-(6-(4-(3,5- difluorobenzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 511.1(M + H) 448

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-((1-methyl-1H- pyrazol-4-yl)methyl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 479.2 (M + H) 449

4-(6-(4-((1-methyl-1H- imidazol-4- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 479.2 (M + H) 450

4-(6-(4-(3- methoxybenzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 505.2(M + H) 451

4-(6-(4-(2- methoxybenzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 505.2(M + H) 452

4-(6-(4-((2- methoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 506.2 (M + H) 453

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(pyridine-2- ylmethyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 477.1 (M + H)454

4-(6-(4-(2- chlorobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 509.1(M + H) 455

4-(6-(4-(3- chlorobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 509.1(M + H) 456

4-(6-(4-((1-acetylpiperidin- 4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 524.2 (M + H) 457

4-(6-(4-((5-fluoro-2- methoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 524.0 (M + H) 458

4-(6-(4-((5- methoxypyridin-2- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 506.2 (M + H) 459

4-(6-(4-((3,3- difluorocyclobutyl)methyl) piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile489.0 (M + H) 460

4-(6-(4-(2-(dimethyl- amino)benzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 518.0(M + H) 461

4-(6-(4-(4-(dimethyl- amino)benzyl)piperazin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 518.2(M + H) 462

4-(6-(4-((5-fluoropyridin- 2-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 494.1 (M + H) 463

4-(6-(4-((3- methoxypyridin-2- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile formate 506.1 (M + H)

Example 464

4-(6-(4-(2-cyanobenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 50 mg, 0.11 mmol) in DMF (1.1 mL) wastreated with 2-formylbenzonitrile (22 mg, 0.16 mmol) and TEA (46 μL,0.33 mmol). The mixture was acidified to pH 6 with acetic acid, and thenstirred for 2 h at room temperature. NaBH₃CN (14 mg, 0.22 mmol) wasadded to the reaction mixture. The resulting mixture was stirred for 18h at room temperature. The reaction mixture was warmed briefly, filteredto remove particulates, and the filtrate was purified by C18 reversephase chromatography (5-50% ACN/water as the gradient eluent) to affordthe title compound (24.8 mg, 44% yield). MS (apci) m/z=500.2 (M+H).

The compounds in Table PP were prepared according to the methoddescribed for the synthesis of Example 464, replacing2-formylbenzonitrile with the appropriate aldehyde. Reactions weremonitored for completion by LCMS, and reaction times were adjustedaccordingly. The title compounds were cleanly isolated following C18reverse phase chromatography using an appropriate gradient eluent,except where noted.

TABLE PP MS (apci) Ex. # Structure Chemical Name m/z 465*

6-(1-methyl-1H-pyrazol-4-yl)-4- (6-(4-((2-methylpyrimidin-5-yl)methyl)piperazin-1-yl)pyridin- 3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 491.2 (M + H) 466*

6-(1-methyl-1H-pyrazol-4-yl)-4- (6-(4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyridin- 3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 483.2 (M + H) 467

6-(1-methyl-1H-pyrazol-4-yl)-4- (6-(4-((2-methylpyrimidin-4-yl)methyl)piperazin-1-yl)pyridin- 3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 491.2 (M + H) 468

4-(6-(4-(3- cyanobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 500.2 (M + H) 469

4-(6-(4-(4- cyanobenzyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 500.2 (M + H) 470

4-(6-(4-(2,6- dimethylbenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 503.2 (M + H) *purified by an aqueous work up:partitioned between EtOAc and water; aqueous extract was neutralized (topH 7) with saturated NaHCO₃, then extracted with EtOAc, and the combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo prior to chromatographic purification.

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitriledihydrochloride (Example 2; 10 mg, 0.022 mmol) in DMF (0.2 mL) wastreated with nicotinaldehyde (3.5 mg, 0.033 mmol), Me₄N(AcO)₃BH (14 mg,0.22 mmol) and TEA (9.1 μL, 0.066 mmol). The resulting mixture wasstirred for 18 h at room temperature, then purified directly by C18reverse phase chromatography (5-60% ACN/water as the gradient eluent) toafford the title compound (6.5 mg, 63% yield). MS (apci) m/z=476.1(M+H).

Example 472

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrimidin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.128 g, 0.280 mmol) in dry DMA (3 mL) wastreated with TEA (117 μL, 0.840 mmol), Me₄N(AcO)₃BH (147 mg, 0.560 mmol)and 2-pyrimidine carboxaldehyde (60.5 mg, 0.560 mmol). The resultingmixture was stirred for 3 d at room temperature, and then additional TEA(39 μL, 0.280 mmol), Me₄N(AcO)₃BH (73.5 mg, 0.187 mmol) and 2-pyrimidinecarboxaldehyde (20.2 mg, 0.28 mmol) were added. After stirring anadditional 24 h at room temperature, the reaction mixture was quenchedwith water and CHCl₃, and allowed to stir for 20 min. The resultingbiphasic mixture was filtered through a PS frit, and the aqueous layerwas washed with CHCl₃. The organic filtrate was concentrated in vacuo,and the residue was purified by C18 reverse phase chromatography (15-90%ACN/water as the gradient eluent) to afford the title compound (60 mg,45% yield). MS (apci) m/z=477.1 (M+H).

Example 473

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 10 mg, 0.022 mmol) in DMF (0.2 mL) wastreated with picolinaldehyde (3.5 mg, 0.033 mmol), Me₄N(AcO)₃BH (12 mg,0.044 mmol) and TEA (9.1 μL, 0.066 mmol). The resulting mixture wasstirred overnight at room temperature, then purified directly by C18reverse phase chromatography (0-60% ACN/water as the gradient eluent) toafford the title compound (5.5 mg, 53% yield). MS (apci) m/z=476.2(M+H).

Example 474

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.125 g, 0.273 mmol) in dry DMA (2.5 mL) wastreated with TEA (114 μL, 0.820 mmol), Me₄N(AcO)₃BH (144 mg, 0.547 mmol)and 6-methoxynicotinaldehyde (0.0750 g, 0.547 mmol). The resultingmixture was stirred overnight at room temperature, then quenched withwater and CHCl₃ and allowed to stir for 30 min. The resulting biphasicmixture was filtered through a PS frit, and the aqueous layer was washedwith CHCl₃. The organic filtrate was concentrated in vacuo, and theresidue was purified by C18 reverse-phase chromatography (5-90%ACN/water as the gradient eluent) to afford the title compound (56 mg,41% yield). MS (apci) m/z=506.0 (M+H).

Example 475

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridin-3-carbonitriledihydrochloride (Example 2; 0.0208 g, 0.0455 mmol) in dry DMF (0.4 mL)was treated with TEA (19.0 μL, 0.136 mmol), dihydro-2H-pyran-4(3H)-one(15.0 μL, 0.091 mmol) and Me₄N(AcO)₃BH (23.9 mg, 0.091 mmol). Theresulting mixture was stirred overnight at 80° C., and then additionaldihydro-2H-pyran-4(3H)-one (15.0 μL, 0.091 mmol) was added. The reactionmixture was allowed to stir at 80° C. until complete by LCMS, and thencooled to room temperature. The reaction mixture was purified directlyby C18 reverse phase chromatography (10-99% ACN/Water as the gradienteluent) to afford the title compound (4.4 mg, 21% yield). MS (apci)m/z=469.1 (M+H).

Example 476

4-(6-(4-cyclobutylpiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.018 g, 0.0394 mmol) in dry DMF (0.3 mL)was treated with TEA (16.5 μL, 0.118 mmol), cyclobutanone (10.0 μL,0.0787 mmol) and Me₄N(AcO)₃BH (20.7 mg, 0.0787 mmol). The mixture wasstirred overnight at 70° C., and then additional cyclobutanone (10.0 μL,0.0787 mmol) and TEA (25 μL, 0.179 mmol) were added. The reactionmixture was allowed to stir at 80° C. overnight, then cooled to roomtemperature and purified directly by C18 reverse phase chromatography(10-99% ACN/Water as the gradient eluent) to afford the title compound(8 mg, 46% yield). MS (apci) m/z=439.2 (M+H).

Example 477

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 2a; 34.3 mg, 0.0892 mmol) in dry DCM (1.8 mL) was treated withoxetane-3-carbaldehyde (11.5 mg, 0.134 mmol), NaBH(AcO)₃ (28.4 mg, 0.134mmol) and acetic acid (25.5 μL, 0.446 mmol). The resulting reactionmixture was allowed to stir 16 h at room temperature. The reactionmixture was diluted with DCM, and washed with saturated NaHCO₃. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% water/ACN with 0.1% TFA as the gradient eluent) toafford the title compound as the TFA salt. The TFA salt was partitionedbetween 4:1 DCM/iPrOH and saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the title compound (8 mg, 46% yield). MS (apci)m/z=455.2 (M+H).

The compounds in Table QQ were prepared according to the methoddescribed for the synthesis of Example 477, replacingoxetane-3-carbaldehyde with the appropriate aldehyde. Reactions weremonitored for completion by LCMS, and reaction times were adjustedaccordingly. The title compounds were cleanly isolated following C18reverse phase chromatography using an appropriate gradient eluent.

TABLE QQ MS (apci) Ex. # Structure Chemical Name m/z 478

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(2- morpholinoethyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 498.2 (M + H)479

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin- 3-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile441.2 (M + H)

Example 480

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(methylamino)ethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 2a; 41.6 mg, 0.108 mmol) in dry DCM (1.1 mL) was treated withtert-butyl methyl(2-oxoethyl)carbamate (28.1 mg, 0.162 mmol), and thenwith NaBH(AcO)₃ (34.4 mg, 0.162 mmol). The reaction mixture was allowedto stir for 16 h at room temperature. The reaction mixture was dilutedwith DCM and washed with saturated NaHCO₃. The combined organic extractswere dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The residue was dissolved in 1:1 DCM/TFA (1.1 mL), stirred for 30 min atroom temperature, and concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was partitioned between 4:1 DCM/iPrOH and saturated NaHCO₃. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound (24.5 mg, 51% yield).MS (apci) m/z=442.2 (M+H).

Example 481

4-(6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(methylamino)ethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 480; 18.0 mg, 0.0408 mmol) in formic acid (308 μL) was treatedwith formaldehyde (91.9 μL, 1.22 mmol), and stirred at 80° C. for 16 h.The reaction mixture was cooled to room temperature, concentrated invacuo, and purified by C18 reverse phase chromatography (5-95% water/ACNwith 0.1% TFA) to afford the title compound as the TFA salt. The TFAsalt was partitioned between 4:1 DCM/iPrOH and saturated NaHCO₃. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo to afford the title compound (9.8 mg, 53%yield). MS (apci) m/z=456.2 (M+H).

Example 482

4-(6-(4-benzyl-3-oxopiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a microwave vessel, a room temperature solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 50 mg, 0.16 mmol) in DMSO (785 μL) was treated with1-benzylpiperazin-2-one (59.8 mg, 0.314 mmol) and K₂CO₃ (65.1 mg, 0.471mmol). The resulting mixture was subjected to microwave irradiation for4 h at 150° C. The reaction mixture was cooled to room temperature andfiltered. The filtrate was purified directly by C18 reverse phasechromatography (5-65% ACN/water) to afford the title compound (42.4 mg,54% yield). MS (apci) m/z=489.2 (M+H).

Example 483

4-(6-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(1S,4S)-tert-butyl5-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(Example 170; 75 mg, 0.15 mmol) was dissolved in 1:1 DCM/TFA (2.0 mL) atroom temperature. The reaction mixture was stirred for 1 h at roomtemperature, and then concentrated in vacuo. The residue was purified bysilica chromatography (1-30% DCM/MeOH with 2% NH₄OH as the gradienteluent) to afford the title compound (59.8 mg, quantitative yield). MS(apci) m/z=397.2 (M+H).

Step 2: Preparation of4-(6-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(59.8 mg, 0.151 mmol) in DCM (1.5 mL) was treated sequentially with TEA(102 μL, 0.754 mmol) and benzyl bromide (53.7 μL, 0.453 mmol). Thereaction mixture was stirred for 16 h at room temperature, thenconcentrated in vacuo. The residue was purified by C18 reverse phasechromatography (5-95% water/ACN as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was suspended in 4:1DCM/iPrOH and extracted with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to cleanly afford the title compound (35.3 mg, 48% yield). MS(apci) m/z=487.2 (M+H).

The compounds in Table RR were prepared according to the methoddescribed for the synthesis of Example 483, replacing (1S,4S)-tert-butyl5-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(Example 170) with the appropriate amino starting materials. Reactionswere monitored by LCMS, and reaction times were adjusted accordingly tocleanly afford the title compounds.

TABLE RR MS (apci) Ex. # Structure Chemical Name m/z 484

4-(6-(8-benzyl-3,8- diazabicyclo[3.2.1]octan-3- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 501.2(M + H) 485

4-(6-(7-benzyl-2,7- diazaspiro[3.5]nonan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 515.2(M + H)

Example 486

4-(6-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

A room temperature mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 48.1 mg, 0.151 mmol) in s-BuOH (1.5 mL) was treatedwith 3,6-diaza-bicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester(31.5 mg, 0.159 mmol) and DIEA (132 μL, 0.756 mmol). The reactionmixture was stirred for 16 h at 130° C., and then DMSO (1 mL) was addedto alleviate solubility issues. The reaction mixture was stirred for anadditional 24 h at 130° C., after which time additional3,6-diaza-bicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (32mg, 0.16 mmol) and DIEA (132 μL, 0.756 mmol) were added. The reactionmixture was stirred for an additional period of 60 h at 130° C., thencooled to room temperature, diluted with EtOAc, and washed successivelywith water and brine. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford thetitle compound which was directly carried on to Step 2 without furtherpurification. MS (apci) m/z=497.2 (M+H).

Step 2: Preparation of4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The tert-butyl3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylateresidue was dissolved in 1:1 DCM/TFA (2.0 mL), stirred for 1 h at roomtemperature, then concentrated in vacuo. The residue was purified bysilica chromatography (1-30% DCM/MeOH with 2% NH₄OH as the gradienteluent) to cleanly afford the title compound (59.9 mg, quantitativeyield). MS (apci) m/z=397.2 (M+H).

Example 487

4-(6-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl6-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

A room temperature mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; (38.7 mg, 0.122 mmol) in DMSO (1.2 mL) was treatedwith 3,6-diaza-bicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester(25.3 mg, 0.128 mmol) and DIEA (106 μL, 0.608 mmol). The reactionmixture was stirred for 16 h at 130° C., and then additional3,6-diaza-bicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (25mg, 0.13 mmol) and DIEA (106 μL, 0.608 mmol) were added. The reactionmixture was stirred for an additional 60 h at 130° C., then cooled toroom temperature, diluted with EtOAc, and washed successively with waterand brine. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo to afford the title compoundwhich was directly carried on to Step 2 without further purification. MS(apci) m/z=497.2 (M+H).

Step 2: Preparation of4-(6-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

tert-butyl6-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylatewas dissolved in 1:1 DCM/TFA (2.0 mL), stirred for 1 h at roomtemperature, and then concentrated in vacuo. The residue was purified bysilica chromatography (1-30% DCM/MeOH with 2% NH₄OH as the gradienteluent) to cleanly afford the title compound (48.2 mg, quantitativeyield). MS (apci) m/z=397.2 (M+H).

Example 488

4-(6-(3,8-Diazabicyclo[3.2.1]octan-8-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

A room temperature mixture of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 48.1 mg, 0.151 mmol) in DMSO (1.2 mL) was treated withtert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (49.9 mg, 0.235mmol) and DIEA (102 μL, 0.587 mmol). The reaction mixture was stirredfor 60 h at 130° C., then cooled to room temperature, diluted with EtOAcand washed successively with water and brine. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica chromatography (5-50%DCM/Acetone as the gradient eluent) to afford the title compound whichwas directly carried on to Step 2. MS (apci) m/z=511.2 (M+H).

Step 2: Preparation of4-(6-(3,8-Diazabicyclo[3.2.1]octan-8-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

tert-Butyl8-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylatewas dissolved in 1:1 DCM/TFA (2.0 mL), stirred for 30 min at roomtemperature and then concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(20.4 mg, 42% yield). MS (apci) m/z=411.1 (M+H).

Example 489

4-(6-(6-benzyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 486; 59.9 mg, 0.151 mmol) in DCM (1.5 mL) was treatedsequentially with TEA (102 μL, 0.755 mmol) and benzyl bromide (53.8 μL,0.453 mmol). The reaction mixture was stirred 16 h at room temperature,then concentrated in vacuo. The residue was purified by C18 reversephase chromatography (5-95% water/ACN with 0.1% TFA as the gradienteluent) to afford the title compound as the TFA salt. The TFA salt wassuspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (1-30% DCM/MeOH with 2% NH₄OH as the gradient eluent) tocleanly afford the title compound (9.3 mg, 13% yield). MS (apci)m/z=487.2 (M+H).

The compounds in Table SS were prepared according to the methoddescribed for the synthesis of Example 489, replacing4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilewith the appropriate amino starting materials. The title compounds wereisolated cleanly following the free base work up (i.e. the final silicachromatographic purification was omitted).

TABLE SS MS (apci) Ex. # Structure Chemical Name m/z 490

4-(6-(3-benzyl-3,6- diazabicyclo[3.1.1]heptan- 6-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 487.2(M + H) 491

4-(6-(3-benzyl-3,8- diazabicyclo[3.2.1]octan-8- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 501.2(M + H)

Example 492

4-(6-(2-(cyclopropanecarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 215; 5.4 mg, 0.011 mmol) in DMA (0.2 mL) wastreated sequentially with DIEA (11.4 μL, 0.065 mmol), thencyclopropanecarbonyl chloride (3.0 μL, 0.033 mmol). The reaction mixturewas stirred for 1 h at room temperature, then diluted with water (2 mL)and stirred overnight. The reaction mixture was vacuum filtered. Theisolated solids were rinsed with water and Et₂O, and dried in vacuo toafford the title compound (3.9 mg, 73% yield). MS (apci) m/z=493.1(M+H).

The compounds in Table TT were prepared according to the methoddescribed for the synthesis of Example 492, replacingcyclopropanecarbonyl chloride with the appropriate acid chloridestarting material, using either DMF or DMA as the reaction solvent andeither DIEA or TEA as the base. Reactions were monitored by LCMS, andreaction times were adjusted accordingly. Title compounds were cleanlyisolated by filtration after an aqueous quench, unless otherwise noted.

TABLE TT MS (apci) Ex. # Structure Chemical Name m/z 493

4-(6-(2- (cyclobutanecarbonyl)-2,7- diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 507.1 (M + H) 494*

4-(6-(2-(2- (dimethylamino)acetyl)- 2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 510.2 (M + H) 495

4-(6-(2- (cyclohexanecarbonyl)-2,7- diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 535.2 (M + H) 496

4-(6-(2-(2-ethylbutanoyl)- 2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 523.2 (M + H) 497

4-(6-(2-(2- cyclopentylacetyl)-2,7- diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 535.2 (M + H) 498

4-(6-(2-(2- cyclohexylacetyl)-2,7- diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 549.2 (M + H) *Following aqueous quench, the reactionmixture was directly subjected to C18 reverse phase chromatographicpurification utilizing an appropriate gradient eluent to cleanly affordthe title compound.

Example 499

Cyclopentyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

A room temperature solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 215; 8 mg, 0.016 mmol) in DMA (0.3 mL) wastreated sequentially with DIEA (28 μL, 0.16 mmol), then cyclopentylcarbonochloridate (12 mg, 0.080 mmol). The reaction mixture was stirred3 d at room temperature, and then diluted with water (2 mL). Theresulting white suspension was filtered. The solid was collected, rinsedwith water and Et₂O, and dried in vacuo. The crude solid was purified bysilica chromatography (0-100% acetone/hexanes as the gradient eluent) tocleanly afford the title compound (2.1 mg, 24% yield). MS (apci)m/z=537.2 (M+H).

Example 500

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(2-(pyrrolidine-1-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 215; 5.6 mg, 0.011 mmol) in DMA (0.2 mL) wastreated sequentially with DIEA (12 μL, 0.068 mmol) andpyrrolidine-1-carbonyl chloride (3.0 mg, 0.023 mmol). The reactionmixture was stirred 1 h at room temperature before diluting with water(2 mL). The reaction mixture was stirred overnight, and then thesuspension was filtered. The solids were collected and rinsed with waterand Et₂O. The filtrate was filtered again, rinsing the solids rinsedwith water and Et₂O. The collected solids were combined and dried invacuo to afford the title compound (2.1 mg, 36% yield). MS (apci)m/z=522.2 (M+H).

The compounds in Table UU were according to the method described for thesynthesis of Example 500, replacing pyrrolidine-1-carbonyl chloride withthe appropriate acid halide starting material. Reactions were monitoredby LCMS and reaction times/temperatures were adjusted accordingly. Titlecompounds were cleanly isolated following filtration except where noted.

TABLE UU MS (apci) Ex. # Structure Chemical Name m/z 501*

7-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N- dimethyl-2,7- diazaspiro[3.5]nonane-2-carboxamide 496.1 (M + H) 502

7-(5-(3-cyano-6-(1-methyl- 1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N- diethyl-2,7- diazaspiro[3.5]nonane-2-carboxamide 524.2 (M + H) *purified by C18 reverse phase chromatography(5-90% ACN/water as the gradient eluent)

Example 503

4-(6-(2-benzyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A room temperature solution of tert-butyl7-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(Example 214; 56 mg, 0.11 mmol) in DCM (4.0 mL) was treated with TFA (2mL, 26 mmol). The reaction mixture was stirred for 30 min at roomtemperature, then concentrated in vacuo to afford the title compound asthe putative TFA salt (45 mg, quantitative yield). This material wascarried on to Step 2 without further purification. MS (apci) m/z=425.2(M+H)

Step 2: Preparation of4-(6-(2-benzyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate (45 mg, 0.1 mmol) in DMF (2 mL) was treatedsequentially with benzyl bromide (40.3 μL, 0.317 mmol) and TEA (102 μL,0.754 mmol). The reaction mixture was stirred overnight at roomtemperature, and then additional benzyl bromide (37.7 μL, 0.339 mmol)and TEA (30.6 μL, 0.226 mmol) were added. The resulting mixture wasstirred for another 5 h at room temperature. The reaction mixture wasdiluted with EtOAc, and washed with water. The combined organic extractswere dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by silica chromatography (eluting with astepped gradient of DCM/MeOH (50:1) then DCM/MeOH (25:1)) to cleanlyafford the title compound (10 mg, 18% yield). MS (apci) m/z=515.2 (M+H).

Example 504

tert-Butyl9-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)-2,9-diazaspiro[5.5]undecane-2-carboxylate

In a microwave vessel, a room temperature solution of tert-butyl2,9-diazaspiro[5.5]undecane-2-carboxylate (95.89 mg, 0.3770 mmol) andDIEA (43.89 μL, 0.2513 mmol) in DMSO (1.00 mL) was treated with4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile(Intermediate P6; 40.00 mg, 0.1257 mmol) and subjected to microwaveirradiation for 2 h at 125° C. After cooling to room temperature, thereaction mixture was directly purified by reverse-phase preparative HPLC(using 10 to 80% ACN/water as the gradient eluent) to afford the titlecompound (10 mg, 14% yield). MS (apci) m/z=553.3 (M+H).

The compounds in Table VV were prepared according the method describedfor the synthesis of Example 504, replacing tert-butyl2,9-diazaspiro[5.5]undecane-2-carboxylate with the appropriate aminestarting material. Reactions were monitored by LCMS, and reaction timeswere adjusted as necessary. Products were purified by reverse-phasepreparative HPLC utilizing an appropriate gradient eluent to cleanlyafford the title compounds.

TABLE VV MS (apci) Ex. # Structure Chemical Name m/z 505

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4- (tetrahydrofuran-3-yl)piperazin-1- yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrilebis(2,2,2- trifluoroacetate) 455.2 (M + H) 506

tert-butyl (2-(4-(5-(3- cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyridin-4-yl)pyridin-2- yl)piperazin-1-yl)ethyl)carbamate 528.2 (M + H) 507

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4- (phenylamino)piperidin-1-yl)pyridin-3- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 475.2 (M + H)508

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(4- phenoxypiperidin-1- yl)pyridin-3-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 476.1 (M + H) 509

4-(6-(4-(4- chlorophenoxy)piperidin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 509.9(M + H) 510

4-(6-(4-hydroxy-4- (trifluoromethyl)piperidin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 468.3 (M + H) 511

tert-butyl 9-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate 553.3 (M + H) 512

tert-butyl 2-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,9- diazaspiro[5.5]undecane-9-carboxylate 553.3 (M + H) 513

tert-butyl 8-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-1,8- diazaspiro[4.5]decane-1- carboxylate539.2 (M + H) 514

tert-butyl 7-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-1,7- diazaspiro[4.5]decane-1- carboxylate539.2 (M + H) 515

tert-butyl 7-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-1,7- diazaspiro[3.5]nonane- 1-carboxylate525.2 (M + H) 516

tert-butyl (7-(5-(3- cyano-6-(1-methyl-1H- pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-7- azaspiro[3.5]nonan-2- yl)carbamate539.2 (M + H) 517

tert-butyl 2-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,8- diazaspiro[4.5]decane-8- carboxylate539.2 (M + H) 518

tert-butyl 2-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,7- diazaspiro[4.5]decane-7- carboxylate539.3 (M + H) 519

tert-butyl 7-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,7- diazaspiro[4.4]nonane- 2-carboxylate525.2 (M + H) 520

tert-butyl 7-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-1,7- diazaspiro[4.4]nonane- 1-carboxylate525.2 (M + H) 521

tert-butyl 6-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,6- diazaspiro[3,4]octane-2- carboxylate511.1 (M + H) 522

tert-butyl 2-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,6- diazaspiro[3.5]nonane- 6-carboxylate525.2 (M + H) 523

tert-butyl 2-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,5- diazaspiro[3.5]nonane- 5-carboxylate525.2 (M + H) 524

tert-butyl 2-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,5- diazaspiro[3,4]octane-5- carboxylate511.1 (M + H) 525

benzyl 2-(5-(3-cyano-6- (1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,5- diazaspiro[3,4]octane-5- carboxylate2,2,2- trifluoroacetate 545.3 (M + H) 526

tert-butyl 6-(5-(3-cyano- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-2,6- diazaspiro[3.3]heptane- 2-carboxylate497.1 (M + H) 527

4-(6-(7-oxa-2- azaspiro[3.5]nonan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 426.1 (M + H) 528

4-(6-(6-oxa-2- azaspiro[3,4]octan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 412.1 (M + H) 529

4-(6-(7-oxa-2- azaspiro[4.5]decan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 440.2(M + H) 530

4-(6-(2-oxa-7- azaspiro[4.4]nonan-7- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 426.2 (M + H) 531

4-(6-(3-hydroxy-3- (trifluoromethyl)pyrrolidin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 454.2 (M + H) 532

4-(6-(2-(4- fluorophenyl)pyrrolidin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 464.2 (M + H) 533

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(3- phenylpyrrolidin-1- yl)pyridin-3-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 2,2,2-trifluoroacetate 446.2(M + H) 534

4-(6-(4-(4- chlorophenyl)piperidin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile2,2,2-trifluoroacetate 494.3 (M + H) 535

4-(6-(4-benzylpiperidin- 1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 474.1 (M + H) 536

4-(6-(4-(4- chlorobenzyl)piperidin- 1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3-carbonitrile 508.0(M + H)

Example 537

4-(6-(2,9-diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A room temperature mixture of tert-butyl9-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,9-diazaspiro[5.5]undecane-2-carboxylate(Example 504, 3 mg, 0.005 mmol) in DCM (133 μL) was treated with HCl iniPrOH [5 N, IPA] (109 μL, 0.543 mmol). After stirring at roomtemperature for 2 h, the reaction mixture was concentrated in vacuo toafford the title compound (2.85 mg, 98% yield). MS (apci) m/z=453.2(M+H).

The compounds in Table WW were prepared according to the methoddescribed for the synthesis of Example 537, replacing9-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-2,9-diazaspiro[5.5]undecane-2-carboxylatewith the appropriate t-Butylcarboxylate from Table VV. Reactions weremonitored by LCMS, and timing of additions, and reaction times wereadjusted as necessary. Products were isolated by vacuum filtration,cleanly providing the title compounds.

TABLE WW MS (apci) Ex. # Structure Chemical Name m/z 538

4-(6-(4-(2- aminoethyl)piperazin-1- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 428.1 (M + H) 539

4-(6-(3,9- diazaspiro[5.5]undecan-3- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 453.2 (M + H) 540

4-(6-(2,9- diazaspiro[5.5]undecan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 453.2 (M + H) 541

4-(6-(1,8- diazaspiro[4.5]decan-8- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 439.1 (M + H) 542

4-(6-(1,7- diazaspiro[4.5]decan-7- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 439.2 (M + H) 543

4-(6-(1,7- diazaspiro[3.5]nonan-7- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 425.1 (M + H) 544

4-(6-(2-amino-7- azaspiro[3.5]nonan-7- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 439.2 (M + H) 545

4-(6-(2,8- diazaspiro[4.5]decan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 439.1 (M + H) 546

4-(6-(2,7- diazaspiro[4.5]decan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 439.2 (M + H) 547

4-(6-(2,7- diazaspiro[4.4]nonan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 425.2 (M + H) 548

4-(6-(1,7- diazaspiro[4.4]nonan-7- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 425.1 (M + H) 549

4-(6-(2,6- diazaspiro[3.4]octan-6- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 411.1 (M + H) 550

4-(6-(2,7- diazaspiro[3.5]nonan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 425.1 (M + H) 551

4-(6-(2,6- diazaspiro[3.5]nonan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 425.1 (M + H) 552

4-(6-(2,5- diazaspiro[3.5]nonan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 425.1 (M + H) 553

4-(6-(2,5- diazaspiro[3.4]octan-2- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitriledihydrochloride 411.1 (M + H)

Example 554

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (5 mg, 0.012 mmol) in dry DMF (200 μL) and TEA (16 μL,0.12 mmol) was treated with 0.1 M iodomethane in MTBE (240 μL, 0.024mmol). The reaction mixture was stirred overnight at room temperature,and then purified directly by C18 reverse phase chromatography (10-99%ACN/Water as the gradient eluent) to afford the title compound (1.7 mg,33% yield). MS (apci) m/z=439.1 (M+H).

The compounds in Table XX were prepared according to the methoddescribed for the synthesis of 554 (except where noted), replacing4-(6-(2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride with the appropriate amine dihydrochloride starting fromTable WW. Reactions were monitored by LCMS, and reaction times andtemperatures were adjusted accordingly. The title compounds were cleanlyisolated following C18 reverse phase chromatography utilizing anappropriate gradient eluent.

TABLE XX MS (apci) Ex # Structure Chemical Name m/z 555 

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(9-methyl-2,9-diazaspiro[5.5]undecan-2- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 467.2 (M + H) 556 

6-(1-methyl-1H-pyrazol-4- yl)-4-(6-(2-methyl-2,9-diazaspiro[5.5]undecan-9- yl)pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 467.2 (M + H) 557*

4-(6-(1-methyl-1,7- diazaspiro[4.5]decan-7- yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile 453.2(M + H) *Additional iodomethane (1 eq), TEA (1 eq) and DMF were addedafter 24 h, and after an additional 48 h reaction mixture was purifiedas noted in all other cases.

Example 558

4-(6-(2-benzyl-2,6-diazaspiro[3.4]octan-6-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(2,6-diazaspiro[3.4]octan-6-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 549; 25 mg, 0.052 mmol) in DMF (2 mL) wastreated sequentially with benzyl bromide (20 μL, 0.32 mmol) and TEA (721μL, 0.517 mmol). The reaction mixture was stirred for 1 h at roomtemperature, then diluted with EtOAc and washed with water. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(eluting with a stepped gradient of DCM/MeOH (50:1) then DCM/MeOH(25:1)) to cleanly afford the title compound (8 mg, 31% yield). MS(apci) m/z=501.2 (M+H).

Example 559

4-(6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

(1S,4S)-tert-butyl5-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(Example 526; 7.5 mg, 0.015 mmol) was dissolved in 1:1 DCM/TFA (0.3 mL).The reaction mixture was diluted with 4:1 DCM/iPrOH and extracted withsaturated NaHCO₃. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to cleanly affordthe title compound (6 mg, quantitative yield). MS (apci) m/z=397.1(M+H).

Example 560

4-(6-(6-benzyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 559; 6.0 mg, 0.0151 mmol) in DCM (0.3 mL) was treatedsequentially with TEA (10.3 μL, 0.755 mmol) and benzyl bromide (5.39 μL,0.0454 mmol). The reaction mixture was stirred for 16 h at roomtemperature and then concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(4.4 mg, 54% yield). MS (apci) m/z=487.2 (M+H).

Example 561

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-hydroxyethyl)-N-isopropylpiperidine-4-carboxamide2,2,2-trifluoroacetate

2-(Isopropylamino)ethanol (0.014 mL, 0.12 mmol), DIEA (0.051 mL, 0.29mmol), and HATU (45 mg, 0.12 mmol) were added sequentially to a roomtemperature solution of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid (Example 231, Step 1; 25 mg, 0.058 mmol) in DMA (2 mL). Afterstirring at room temperature overnight, the reaction mixture wasquenched with water and then extracted with EtOAc. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated invacuo and purified by C18 reverse phase chromatography (5-95% water/ACNwith 0.1% TFA as the gradient eluent) to afford the title compound asthe TFA salt (4.7 mg, 15% yield). MS (apci) m/z=513.3 (M+H).

Example 562

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)-N,N-dimethylpiperidine-4-carboxamide2,2,2-trifluoroacetate

The title compound was isolated as a byproduct of the reaction ofExample 561 (8.8 mg, 33% yield). MS (apci) m/z=455.2 (M+H).

Example 563

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(cyclopropylmethoxy)piperidine-4-carboxamide

O-Cyclopropylmethyl-hydroxylamine hydrochloride (0.015 g, 0.12 mmol),DIEA (0.061 mL, 0.35 mmol), and HATU (45 mg, 0.12 mmol) were addedsequentially to a solution1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylicacid (Example 231, Step 1; 25 mg, 0.058 mmol) in DMA (2 mL). Afterstirring at ambient temperature overnight, the reaction mixture wasquenched with water and extracted with EtOAc. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated invacuo, and purified by silica chromatography (0-50% of 20% MeOH/DCM inEtOAc as the gradient eluent) to afford the title compound (8.5 mg, 28%yield). MS (apci) m/z=497.2 (M+H).

The compounds in Table YY were prepared according to the methoddescribed for the synthesis of Example 563, replacingO-Cyclopropylmethyl-hydroxylamine hydrochloride with the appropriateamines. Reactions were monitored by LCMS, and reaction times wereadjusted accordingly. The title compounds were cleanly isolatedfollowing silica chromatography utilizing an appropriate gradienteluent.

TABLE YY MS (apci) Ex # Structure Chemical Name m/z 564

1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N- methoxypiperidine-4- carboxamide 457.2 (M + H) 565

N-(tert-butoxy)-1-(5-(3- cyano-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl) pyridin-2-yl)piperidine- 4-carboxamide 499.3 (M +H) 566

1-(5-(3-cyano-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2- hydroxyethoxy)piperidine- 4-carboxamide 487.2(M + H)

Example 567

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(methylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.030 g, 0.094 mmol) in DMSO (6.28 mL) was treatedwith 4-(methylsulfonyl)piperidine (0.062 g, 0.38 mmol) and K₂CO₃ (0.10g, 0.75 mmol) and stirred overnight at 80° C. The reaction mixture wasadjusted to pH 7 with the addition of saturated NaHCO₃. The resultingsuspension was vacuum filtered and rinsed with water to afford the titlecompound (26 mg, 57% yield). MS (apci) m/z=462.1 (M+H).

Example 568

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-sulfonicacid

A room temperature solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.100 g, 0.314 mmol) in DMSO (2.4 mL) was treated withpiperidine-4-sulfonic acid (0.16 g, 0.94 mmol) and K₂CO₃ (0.13 g, 0.94mmol), then stirred overnight at 110° C. The reaction mixture wasadjusted to pH 7 with 1 M HCl. The resulting suspension was vacuumfiltered through a nylon membrane and rinsed with water to afford thetitle compound (85 mg, 78% yield). MS (apci) m/z=462.1 (M−H).

Example 569

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-4-sulfonamideStep 1: Preparation of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-sulfonylchloride

A room temperature mixture of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-sulfonicacid (Example 568; 0.025 g, 0.054 mmol) in DCE (1.1 mL) was treatedsequentially with SOCl₂ (0.020 mL, 0.27 mmol) and DMF (0.027 mL, 0.054mmol). The resulting mixture was stirred for 3 h at reflux, and thencooled to room temperature. The reaction mixture was concentrated invacuo to afford the crude title compound (25 mg, 96% yield), which wasused directly in the next step without further purification.

Step 2: Preparation of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-4-sulfonamide

A room temperature solution of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)piperidine-4-sulfonylchloride (from Step 1; 25 mg, 0.052 mmol) in DCM (2.6 mL) and DIEA (45μL, 0.259 mmol) was treated with isopropyl amine (8.9 μL, 0.10 mmol).After stirring overnight at room temperature, the reaction mixture wasquenched with water and extracted with DCM. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica gel (0-10% MeOH in DCM) toafford the title compound (12.2 mg, 45% yield). MS (apci) m/z=505.2(M+H)

Example 570

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a microwave vessel, a room temperature solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 30 mg, 0.094 mmol) in DMSO (471 μL) was treated with2-(piperidin-4-ylmethyl)pyridine dihydrochloride (35 mg, 0.14 mmol) andK₂CO₃ (39 mg, 0.28 mmol). The resulting mixture was subjected tomicrowave irradiation for 1 h at 100° C., and then for 12 h at 150° C.The reaction mixture was cooled to room temperature, and filtered. Thefiltrate was purified directly by C18 reverse phase chromatography(5-40% ACN/water) to afford the title compound (15 mg, 33% yield). MS(apci) m/z=475.2 (M+H).

Example 571

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)azetidine-3-carboxylicacid

A room temperature solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.300 g, 0.942 mmol) in DMSO (9.42 mL) was treatedwith azetidine-3-carboxylic acid (0.381 g, 3.77 mmol) and K₂CO_(3(s))(0.521 g, 3.77 mmol), then stirred overnight at 110° C. The reactionmixture was acidified to pH 7 with 1 M HCl. The resulting suspension wasvacuum filtered, and the solids were washed with water to cleanly affordthe title compound (0.281 g, 74.6% yield). MS (apci) m/z=400.2 (M+H).

Example 572

1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylazetidine-3-carboxamide

A room temperature solution of1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)azetidine-3-carboxylicacid (Example 571; 25 mg, 0.0626 mmol) in DMA (2.09 mL) was added DIEA(54.5 μL, 0.313 mmol), propan-2-amine (7.4 mg, 0.125 mmol) and HATU(47.6 mg, 0.125 mmol). The reaction mixture was allowed to stirovernight at room temperature. The reaction mixture was quenched withwater and extracted with EtOAc. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by silica chromatography (0-50% gradient of 20% MeOH/DCM inEtOAc as the eluent) to afford the title compound (8.7 mg, 31% yield).MS (apci) m/z=441.2 (M+H).

Example 573

2-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)azetidin-3-yl)aceticacid

A room temperature solution of4-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.225 g, 0.707 mmol) in DMSO (7.07 mL) was treatedwith azetidin-3-yl-acetic acid hydrochloride (0.4296 g, 2.83 mmol) andK₂CO₃ (0.782 g, 5.66 mmol), then stirred overnight at 110° C. Thereaction mixture was acidified to pH 7 with 1 M HCl. The resultingsuspension was vacuum filtered, and the solids were washed with water tocleanly afford the title compound (0.393 g, quantitative yield). MS(apci) m/z=414.2 (M+H).

Example 574

2-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)azetidin-3-yl)-N-isopropylacetamide

A room temperature solution of2-(1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)azetidin-3-yl)aceticacid (Example 573; 50 mg, 0.121 mmol) in DMA (2.42 mL) was treated withDIEA (0.105 mL, 0.605 mmol), propan-2-amine (14.3 mg, 0.242 mmol) andHATU (92.0 mg, 0.242 mmol). The reaction mixture was allowed to stirovernight at room temperature. The reaction mixture was quenched withwater and extracted with EtOAc. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by silica chromatography (0-50% gradient of 20% MeOH/DCM inEtOAc as the eluent) to afford the title compound (4.6 mg, 8% yield). MS(apci) m/z=455.2 (M+H).

Example 575

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 55.3 mg, 0.150 mmol) in 4:1dioxane/water (1.5 mL) was treated with2-(piperidin-4-yl)pyridine-5-boronic acid (61.4 mg, 0.298 mmol),Pd₂(dba)₃ (6.82 mg, 0.00745 mmol), XPhos (14.2 mg, 0.0298 mmol), andK₂CO₃ (61.8 mg, 0.447 mmol). The reaction mixture was sparged withArgon, sealed, and then stirred 16 h at 100° C. After cooling to roomtemperature, the reaction mixture was diluted with 4:1 DCM/iPrOH andwashed with water. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by C18 reverse phase chromatography (5-95% water/ACN with 0.1%TFA as the gradient eluent) to afford the title compound as the TFAsalt. The TFA salt was suspended in 4:1 DCM/iPrOH and extracted withsaturated NaHCO₃. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to cleanly affordthe title compound (18.1 mg, 32% yield). MS (apci) m/z=384.1 (M+H).

Example 576

4-(6-(1-benzylpiperidin-4-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 575; 18.1 mg, 0.0472 mmol) in DCM (1.0 mL) was treatedsequentially with TEA (32.0 μL, 0.236 mmol) and benzyl bromide (16.8 μL,0.142 mmol). The reaction mixture was stirred for 16 h at roomtemperature and then concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(15.6 mg, 70% yield). MS (apci) m/z=474.2 (M+H).

Example 577

4-(6-(azetidin-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)azetidine-1-carboxylate

A room temperature solution of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate (Intermediate P5; 89.5 mg, 0.241 mmol) in 4:1dioxane:water (2.5 mL) was treated with tert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)azetidine-1-carboxylate(Intermediate R13; 174 mg, 0.482 mmol), Pd₂(dba)₃ (11.0 mg, 0.0120mmol), XPhos (23 mg, 0.0482 mmol), and K₂CO₃ (100 mg, 0.723 mmol). Thereaction mixture was sparged with Argon, sealed, and stirred 16 h at100° C. After cooling to room temperature, the reaction mixture wasdiluted with 4:1 DCM/iPrOH and washed with water. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by C18 reverse phase chromatography(5-95% water/ACN with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was suspended in 4:1DCM/iPrOH and extracted with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford the title compound. MS (apci) m/z=356.1 ((M-Boc)+1).

Step 2: Preparation of4-(6-(3,8-Diazabicyclo[3.2.1]octan-8-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The tert-butyl3-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)azetidine-1-carboxylatewas diluted with 1:1 DCM/TFA (2.0 mL), stirred for 30 min at roomtemperature, and then concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(12.7 mg, 15% yield). MS (apci) m/z=356.1 (M+H).

The compounds in the Table ZZ were prepared according to the methoddescribed for the synthesis of Example 577, replacing tert-butyl3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)azetidine-1-carboxylatein Step 1, with the appropriate boronate ester from Table DD. Reactionprogression was followed by LCMS, and reaction times were adjusted asnecessary. Products in each step were purified according to methoddescribed for the synthesis of Example 577, employing the appropriatestationary phase and gradient eluent.

TABLE ZZ MS (apci) Ex # Structure Chemical Name m/z 578

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(pyrrolidin-3- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 370.1 (M + H) 579

6-(1-methyl-1H-pyrazol- 4-yl)-4-(6-(piperidin-3- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 384.2 (M + H)

Example 580

4-(6-(1-benzylazetidin-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(azetidin-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 577; 12.7 mg, 0.0357 mmol) in DCM (0.7 mL) was treatedsequentially with TEA (24.2 μL, 0.179 mmol) and benzyl bromide (12.7 μL,0.107 mmol). The reaction mixture was stirred for 16 h at roomtemperature, and then concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(4.1 mg, 26% yield). MS (apci) m/z=446.2 (M+H).

The compounds in the Table AAA were prepared according to the methoddescribed for the synthesis of Example 580, replacing4-(6-(azetidin-3-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilewith the appropriate amine from Table ZZ. Products were purifiedaccording to the method described for the synthesis of Example 580,employing the appropriate gradient eluent.

TABLE AAA MS (apci) Ex # Structure Chemical Name m/z 581

4-(6-(1-benzylpiperidin- 3-yl)pyridine-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 474.2 (M + H) 582

4-(6-(1-benzylpyrrolidin- 3-yl)pyridine-3-yl)-6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 460.2 (M + H)

Example 583

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(pyrrolidin-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 578; 31.3 mg, 0.0847 mmol) in 1:1 DCM/MeOH (1.7 mL) was treatedwith 4-formyltetrahydropyran (19.3 mg, 0.169 mmol), NaBH(AcO)₃ (35.9 mg,0.169 mmol) and a drop of acetic acid. The reaction mixture was allowedto stir 16 h at room temperature. The reaction mixture was purifieddirectly by C18 reverse phase chromatography (5->95% water/ACN with 0.1%TFA) to afford the title compound as the TFA salt. The TFA salt wassuspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo to cleanly afford the title compound (29.0 mg,73% yield). MS (apci) m/z=468.2 (M+H).

Example 584

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Following a method similar to that used for Example 583, but replacing4-formyltetrahydropyran with pyrimidine carboxaldehyde, the titlecompound was isolated cleanly (24.2 mg, 46% yield). MS (apci) m/z=462.2(M+H).

Example 585

6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(2-isopropoxyethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 266; 20 mg, 0.041 mmol) in dry DMA (400 μL) wastreated with TEA (76 μL, 0.55 mmol) and 2-(2-bromoethoxy)propane (0.0203g, 0.122 mmol). The resulting reaction mixture was stirred overnight at75° C. The reaction mixture was purified directly by C18 reverse phasechromatography (15-90% ACN/Water as the eluent) to afford the titlecompound (12.4 mg, 60% yield). MS (apci) m/z=507.2 (M+H).

Example 586

6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 266; 10 mg, 0.020 mmol) and Me₄N(AcO)₃BH (16mg, 0.061 mmol) in DMF (0.2 mL) was treated with picolinaldehyde (3.3mg, 0.030 mmol) and TEA (8.5 μL, 0.061 mmol). The resulting mixture wasstirred overnight at room temperature, and then purified directly by C18reverse phase chromatography (0-60% ACN/water as the gradient eluent) toafford the title compound (2.4 mg, 23% yield). MS (apci) m/z=512.2(M+H).

Example 587

4-(6-(4-(2-isopropoxyethyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 271; 21 mg, 0.046 mmol) in dry DMA (400 μL) wastreated with TEA (64 μL, 0.46 mmol) and 2-(2-bromoethoxy)propane (23 mg,0.138 mmol). The resulting reaction mixture was stirred overnight at 75°C. The reaction mixture was purified directly by C18 reverse phasechromatography (15-90% ACN/Water as the eluent) to afford the titlecompound (12.4 mg, 57% yield). MS (apci) m/z=471.2 (M+H).

Example 588

6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-3-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 271; 10 mg, 0.022 mmol) in DMF (0.2 mL) wastreated with picolinaldehyde (3.5 mg, 0.033 mmol), Me₄N(AcO)₃BH (17 mg,0.066 mmol) and TEA (9.1 μL, 0.066 mmol). The resulting mixture wasstirred overnight at room temperature, and then purified directly by C18reverse phase chromatography (0-60% ACN/water as the gradient eluent) toafford the title compound (2.3 mg, 22% yield). MS (apci) m/z=476.2(M+H).

Example 589

tert-Butyl4-(5-(3-cyano-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)piperazine-1-carboxylate

A room temperature solution of3-cyano-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P19; 0.538 g, 1.13 mmol) indioxane (28.2 mL) was treated with tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-carboxylate(0.658 g, 1.69 mmol) and 2 M K₂CO₃ (1.13 mL, 2.25 mmol), then spargedwith N₂ for 5 min. The reaction mixture was treated with XPhos (0.107 g,0.225 mmol) and Pd₂(dba)₃ (0.0516 g, 0.0563 mmol), then sparged with N₂for 5 min, sealed, and stirred overnight at 80° C. After cooling to roomtemperature, the reaction mixture was diluted with water, and extractedwith EtOAc. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was trituratedwith hexanes and vacuum filtered to afford the title compound (0.615 g,92% yield). MS (apci) m/z=591.3 (M+H)

Example 590

6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of tert-butyl4-(5-(3-cyano-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 589; 0.615 g, 1.04 mmol) in DCM (10.4 mL) was treated with TFA(5.21 mL, 1.04 mmol) and stirred for 30 min at room temperature. Thereaction mixture was concentrated in vacuo. The residue was diluted withDCM and concentrated in vacuo to remove residual TFA. The residue waspartitioned between 10% MeOH in DCM and saturated NaHCO₃, and theaqueous phase was extracted with 10% MeOH in DCM. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to cleanly afford the title compound (0.489 g, 96% yield). MS(apci) m/z=491.2 (M+H).

Example 591

4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-(4-benzylpiperazin-1-yl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 590; 0.240 g, 0.489 mmol) in DMA (4.89 mL) was treatedsequentially with TEA (0.341 mL, 2.45 mmol) and benzyl bromide (0.116mL, 0.978 mmol). The reaction mixture was stirred overnight at roomtemperature and then quenched with water, and the biphasic mixture wasextracted with EtOAc. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to cleanly affordthe title compound (0.284 g, quantitative yield). MS (apci) m/z=581.2(M+H).

Step 2: Preparation of4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-(4-Benzylpiperazin-1-yl)pyridin-3-yl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.284 g, 0.489 mmol) was treated with TFA (9.78 mL, 4.89 mmol). Thereaction was stirred overnight at 70° C. and then concentrated in vacuo.The residue was diluted with DCM (15 mL) and treated with saturatedNaHCO₃ (60 mL) and water (5 mL). The biphasic mixture was diluted with20% MeOH/DCM (50 mL), and the resulting suspension was vacuum filtered.The biphasic filtrate was separated, and the organic phase was reserved.The aqueous extracts were washed with 20% MeOH/DCM. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by C18 reverse phase chromatography(0-60% ACN/H₂O as the gradient eluent) to afford the title compound(0.221 g, 98% yield). MS (apci) m/z=461.2 (M+H).

Example 592

(R)-4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 591; 0.014 g, 0.030 mmol) in dry DMF (1 mL) was treated withCs₂CO₃ (0.050 g, 0.15 mmol) and (S)-3-bromo-2-methylpropan-1-ol (16 μL,0.15 mmol). The resulting mixture was stirred for 6 hr at 70° C., andthen quenched with water. The biphasic mixture was extracted with DCMand then filtered through a PS frit. The combined organic extracts thenwere concentrated in vacuo. The residue was purified by C18 reversephase chromatography (10-80% ACN/Water with 0.1% Formic Acid as thegradient eluent) to afford the title compound (10.6 mg, 66% yield). MS(apci) m/z=533.2 (M+H).

Example 593

(S)-4-(6-(4-benzylpiperazin-1-yl)pyridine-3-yl)-6-(1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared according to the method described forthe synthesis of(R)-4-(6-(4-benzylpiperazin-1-yl)pyridine-3-yl)-6-(1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 592), replacing (S)-3-bromo-2-methylpropan-1-ol with(R)-3-bromo-2-methylpropan-1-ol. The crude material was purified by C18reverse phase chromatography (10-80% ACN/Water with 0.1% Formic Acid asthe gradient eluent) to provide the title compound (17.4 mg, 56% yield).MS (apci) m/z=533.2 (M+H).

Example 594

tert-butyl3-(4-(4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridine-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

A room temperature solution of4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile(Example 591; 0.1165, 0.2530 mmol) in dry DMF (0.5 mL) was treated withCs₂CO₃ (0.3778 g, 1.159 mmol) and tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (0.1271 g, 0.5059 mmol). Theresulting mixture was sealed in a pressure tube and stirred overnight at70° C., and then quenched with water. The biphasic mixture was extractedwith EtOAc and then with CHCl₃. The combined organic extracts wereconcentrated in vacuo, and the residue was purified by C18 reverse phasechromatography (5-99%, ACN/Water as the gradient eluent) to afford thetitle compound (26 mg, 17% yield). MS (apci) m/z=616.2 (M+H).

Example 595

6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A room temperature solution of tert-butyl3-(4-(4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(Example 594; 0.024 g, 0.039 mmol) in dry DCM (0.2 mL) was treated with5 M HCl in iPrOH (39 μL, 0.19 mmol). After stirring at room temperaturefor 2 d, additional 5 M HCl in iPrOH (7.8 μL, 0.038 mmol) was added. Thereaction mixture was stirred overnight at room temperature and thenconcentrated in vacuo to afford the title compound as thedihydrochloride salt (25 mg, quantitative yield). MS (apci) m/z=516.2(M+H).

Example 596

4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1-(1-isopropylazetidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 595; 0.007 g, 0.012 mmol) in dry DMF (300 μL)was treated with TEA (17 μL, 0.12 mmol) and 2-iodopropane (3.6 μL, 0.036mmol). The reaction mixture was stirred overnight at 70° C., thendirectly purified by C18 reverse phase chromatography using 5-85%ACN/Water as the gradient eluent and then further purified by C18reverse phase chromatography using 70-99% ACN/Water with 0.1% FormicAcid as the gradient eluent to afford the title compound (1.6 mg, 24%yield). MS (apci) m/z=558.2 (M+H).

Example 597

1-(5-(3-cyano-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-isopropylpiperidine-4-carboxamide

A room temperature solution of3-cyano-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P21; 0.030 g, 0.078 mmol) indioxane (1.95 mL) was treated with(6-(4-ethyl-4-(isopropylcarbamoyl)piperidin-1-yl)pyridin-3-yl)boronicacid (Intermediate R17; 0.037 g, 0.12 mmol) and 2 M K₂CO₃ (0.078 mL,0.16 mmol), then sparged with N₂ for 5 min. The reaction mixture wastreated with XPhos (0.0074 g, 0.016 mmol) and Pd₂(dba)₃ (0.0036 g,0.0039 mmol), then sparged with N₂ for 5 min, sealed, and stirredovernight at 80° C. After cooling to room temperature, the reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gel (0-10%MeOH in DCM) to afford the title compound (0.0187 g, 47% yield). MS(apci) m/z=511.3 (M+H).

Example 598

(S)-6-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of3-cyano-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P21; 0.030 g, 0.078 mmol) indioxane (1.95 mL) was treated with(S)-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridine-3-yl)boronicacid (Intermediate R18; 0.039 g, 0.12 mmol) and 2 M K₂CO₃ (0.078 mL,0.16 mmol), then sparged with N₂ for 5 min. The reaction mixture wastreated with XPhos (0.0074 g, 0.016 mmol) and Pd₂(dba)₃ (0.0036 g,0.0039 mmol), then sparged with N₂ for 5 min, sealed, and stirredovernight at 80° C. After cooling to room temperature, the reactionmixture was diluted with water, and extracted with EtOAc. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica chromatography(0-50% gradient of 20% MeOH/DCM in EtOAc as the gradient eluent) toafford the title compound (24.2 mg, 57% yield). MS (apci) m/z=526.3(M+H).

Example 599

1-(5-(3-cyano-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-ethyl-N-isopropylpiperidine-4-carboxamide

A room temperature solution of3-cyano-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P23; 0.030 g, 0.078 mmol) indioxane (1.95 mL) was treated with(6-(4-ethyl-4-(isopropylcarbamoyl)piperidin-1-yl)pyridine-3-yl)boronicacid (Intermediate R17; 0.037 g, 0.12 mmol) and 2 M K₂CO₃ (0.078 mL,0.16 mmol), then sparged with N₂ for 5 min. The reaction mixture wastreated with XPhos (0.0074 g, 0.016 mmol) and Pd₂(dba)₃ (0.0036 g,0.0039 mmol), then sparged with N₂ for 5 min, sealed, and stirredovernight at 80° C. After cooling to room temperature, the reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(0-50% gradient of 20% MeOH/DCM in EtOAc as the eluent) to afford thetitle compound (0.0357 g, 89% yield). MS (apci) m/z=511.3 (M+H).

Example 600

(S)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of3-cyano-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate (Intermediate P23; 0.030 g, 0.078 mmol) indioxane (1.9 mL) was treated with(S)-(6-(4-(3-methoxypyrrolidine-1-carbonyl)piperazin-1-yl)pyridine-3-yl)boronicacid (Intermediate R18; 0.039 g, 0.12 mmol) and 2 M K₂CO₃ (0.078 mL,0.16 mmol) and sparged with N₂ for 5 min. The reaction mixture wastreated with XPhos (0.0074 g, 0.016 mmol) and Pd₂(dba)₃ (0.0036 g,0.0039 mmol), then sparged with N2 for 5 min, sealed, and stirredovernight at 80° C. After cooling to room temperature, the reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(0-50% gradient of 20% MeOH/DCM in EtOAc as the eluent) to afford thetitle compound (7.7 mg, 19% yield). MS (apci) m/z=526.3 (M+H).

Example 601

6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-(5-(3-cyano-6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A room temperature solution of tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)piperazine-1-carboxylate(Intermediate P14; 98.6 mg, 0.178 mmol) in 4:1 dioxane/water (2.0 mL)was treated with1-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate R22; 46.3 mg, 0.196 mmol), Pd₂(dba)₃ (8.17 mg, 0.00892mmol), XPhos (17.0 mg, 0.0357 mmol) and K₂CO_(3(s)) (74.0 mg, 0.535mmol). The reaction mixture was sparged with Argon, sealed, and stirredfor 16 h at 100° C. After cooling to room temperature, the reactionmixture was diluted with 4:1 DCM/iPrOH and washed with water. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (5-60% DCM-Acetone as the gradient eluent) to afford thetitle compound (44.6 mg, 61% yield). MS (apci) m/z=413.2 (M+H).

Step 2: Preparation of6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of tert-butyl4-(5-(3-cyano-6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)piperazine-1-carboxylate(Step 1; 44.6 mg, 0.108 mmol) in 1:1 DCM/TFA (3.0 mL) was stirred for 30min at room temperature and then concentrated in vacuo. The residue waspurified by silica chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(44.6 mg, 61% yield). MS (apci) m/z=591.3 (M+H).

The compounds in Table BBB were prepared according to the methoddescribed for the synthesis of Example 601, replacing1-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith the appropriate boronate ester starting materials from Table EE.Reactions were monitored by LCMS, and reaction times were adjustedaccordingly.

TABLE BBB MS (apci) Ex # Structure Chemical Name m/z 602

6-(3-ethyl-1-methyl-1H- pyrazol-4-yl)-4-(6- (piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 413.2 (M + H) 603

6-(1-isopropyl-1H-pyrazol- 4-yl)-4-(6-(piperazin-1- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 413.2 (M + H) 604

6-(1-isopropyl-1H-pyrazol- 4-yl)-4-(6-(piperazin-1- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 427.2 (M + H) 605

4-(6-(piperazin-1- yl)pyridin-3-yl)-6-(1,3,5- trimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 413.2 (M + H) 606

6-(1-isopropyl-3-methyl- 1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile427.2 (M + H) 607

6-(1-(tert-butyl)-3-methyl- 1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile441.2 (M + H) 608

6-(1,3-diethyl-1H-pyrazol- 4-yl)-4-(6-(piperazin-1- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 427.2 (M + H)

Example 609

4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 601; 28.8 mg, 0.0698 mmol) in DCM (1.4 mL) was treatedsequentially with TEA (47.4 μL, 0.349 mmol) and benzyl bromide (24.9 μL,0.209 mmol). The reaction mixture was stirred for 16 h at roomtemperature and then concentrated in vacuo. The residue was purified byC18 reverse phase chromatography (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and extracted with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(17.9 mg, 51% yield). MS (apci) m/z=503.2 (M+H).

Except where noted, the compounds in Table CCC were prepared accordingto the method described for the synthesis of Example 609, replacing6-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilewith the appropriate amino starting materials. Reactions were monitoredby LCMS, and reaction times were adjusted accordingly to cleanly affordthe title compounds.

TABLE CCC MS (apci) Ex # Structure Chemical Name m/z 610 

4-(6-(4-benzylpiperazin-1- yl)pyridin-3-yl)-6-(3-ethyl-1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 503.2(M + H) 611 

4-(6-(4-benzylpiperazin-1- yl)pyridin-3-yl)-6-(1-isopropyl-1H-pyrazol-4- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 503.2(M + H) 612 

4-(6-(4-benzylpiperazin-1- yl)pyridin-3-yl)-6-(1- isobutyl-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 517.2 (M + H) 613 

4-(6-(4-benzylpiperazin-1- yl)pyridin-3-yl)-6-(1,3,5-trimethyl-1H-pyrazol-4- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 503.2(M + H) 614*

4-(6-(4-benzylpiperazin-1- yl)pyridin-3-yl)-6-(1- isopropyl-3-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3- carbonitrile 517.3 (M + H) 615 

4-(6-(4-benzylpiperazin-1- yl)pyridin-3-yl)-6-(1,3-diethyl-1H-pyrazol-4- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 517.3(M + H) 616 

4-(6-(4-benzylpiperazin-1- yl)pyridin-3-yl)-6-(1-(tert-butyl)-3-methyl-1H- pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 531.2 (M + H) *Aqueous free-basing step was replaced with asilica chromatography using 1-30% DCM/MeOH with 2% NH₄OH as the gradienteluent for free-basing the TFA salt.

Example 617

tert-butyl4-(5-(3-cyano-6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A room temperature solution of tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)piperazine-1-carboxylate(Intermediate P14; 60.0 mg, 0.11 mmol) in 4:1 dioxane/water (8 mL) wastreated with3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(40 mg, 0.16 mmol), K₂CO₃ (30 mg, 0.22 mmol), XPhos (10 mg, 0.022 mmol)and Pd₂(dba)₃ (5.0 mg, 0.0054 mmol). The mixture was sparged with Argonfor 10 min, sealed, and stirred overnight at 90° C. After cooling toroom temperature, the reaction mixture was diluted with water andextracted with EtOAc. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica chromatography (using 30-50% EtOAc in Hexanes as theeluent) to afford the title compound (0.032 g, 56% yield). MS (apci)m/z=525.3 (M+H).

Example 618

6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of tert-butyl4-(5-(3-cyano-6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 617; 32 mg, 0.061 mmol) in DCM (4 mL) was treated with TFA (2mL, 0.40 mmol) and stirred for 30 min at room temperature. The reactionmixture was concentrated in vacuo. The residue was dissolved in 20%iPrOH in DCM and extracted with 10% NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford the title compound in sufficient purity (0.024 g, 92%yield). MS (apci) m/z=425.2 (M+H).

Example 619

4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 618; 12 mg, 0.028 mmol) in DMF (2 mL) was treated sequentiallywith benzyl bromide (10.7 μL, 0.0905 mmol) and TEA (19.7 μL, 0.141mmol). The reaction mixture was stirred overnight at room temperature,then diluted with EtOAc and washed with water. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica chromatography (20% Hexanes inEtOAc as the gradient eluent) to cleanly afford the title compound (10mg, 69% yield). MS (apci) m/z=515.2 (M+H).

Example 620

6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(12 mg, 0.028 mmol) in DMF (2 mL) was treated successively withpicolinaldehyde (11 mg, 0.099 mmol) and acetic acid (17 mg, 0.28 mmol).The resulting reaction mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with EtOAc and washed withwater. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by reversephase HPLC (5-95% water/ACN with 0.1% TFA as the gradient eluent) toafford the title compound (10 mg, 69% yield). MS (apci) m/z=516.3 (M+H).

Example 621

tert-butyl4-(5-(3-cyano-6-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P14; 150 mg, 0.271 mmol),3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (85.1mg, 0.407 mmol), Pd(PPh₃)₄ (31.4 mg, 0.0271 mmol) and 2 M Na₂CO₃ (679μL, 1.36 mmol) in dioxane (20 mL) was sparged with N_(2(g)), thensealed, and stirred 4 h at 100° C. The reaction mixture was cooled toroom temperature, diluted with water (10 mL) and extracted with EtOAc.The combined organic extracts were filtered through PS paper,concentrated in vacuo, and purified by silica chromatography (0-100%EtOAc/hexanes as the eluent) to afford the title compound (124 mg, 94%yield). MS (apci) m/z=486.2 (M+H).

The compound in Table DDD was prepared according to the method describedfor the synthesis of Example 621, replacing3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole withthe appropriate boronic ester.

TABLE DDD MS (apci) Ex # Structure Chemical Name m/z 622

tert-butyl 4-(5-(3-cyano-6- (3-methyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)piperazine-1- carboxylate 485.2 (M + H)

Example 623

tert-butyl4-(5-(3-cyano-6-(1,5-dimethyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-(3-cyano-6-(3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)piperazine-1-carboxylate(200 mg, 0.413 mmol), CH₃I (38.6 μL, 0.619 mmol) and Cs₂CO₃ (538 mg,1.65 mmol) in DMF (2 mL) was stirred overnight at room temperature. Thereaction was diluted with water (20 mL), and the resulting precipitatewas vacuum filtered. The solids were washed with water and hexanes andthen air-dried to cleanly afford the title compound (182 mg, 88% yield).MS (apci) m/z=499.2 (M+H).

Example 624

6-(2-methyloxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A room temperature solution of tert-butyl4-(5-(3-cyano-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-2-yl)piperazine-1-carboxylate(120 mg, 0.247 mmol) in DCM (2 mL) was treated with 5 M HCl in iPrOH(49.4 μL, 0.247 mmol). The reaction was stirred for 72 h at roomtemperature and then filtered. The solid was washed with Et₂O andair-dried to afford the title compound (50 mg, 53% yield). MS (apci)m/z=386.1 (M+H).

The compounds in Table EEE were prepared using a method similar to thatused for Example 624, replacing tert-butyl4-(5-(3-cyano-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)piperazine-1-carboxylatewith the appropriate Boc-protected piperazine compound. Reactions werefollowed by LCMS, and reaction times were adjusted as necessary.

TABLE EEE MS (apci) Ex # Structure Chemical Name m/z 625*

6-(3-methylisoxazol-5-yl)- 4-(6-(piperazin-1- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile hydrochloride 386.1 (M + H)626 

6-(3-methyl-1H-pyrazol-5- yl)-4-(6-(piperazin-1- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile dihydrochloride 385.2 (M + H)627 

6-(1,5-dimethyl-1H- pyrazol-3-yl)-4-(6- (piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile dihydrochloride 399.1 (M + H)*The starting material, tert-butyl4-(5-(3-cyano-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate,was prepared according to example 621.

Example 628

4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(2-methyloxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 624; 12 mg, 0.0262 mmol) in DMF (0.2 mL) wastreated with TEA (10.9 μL, 0.0785 mmol) and (bromomethyl)benzene (4.04μL, 0.0340 mmol). The resulting mixture was stirred for 1 h at roomtemperature and then directly purified by C18 reverse phasechromatography (0-60% ACN/water as the gradient eluent) to afford thetitle compound (6.8 mg, 55% yield). MS (apci) m/z=476.2 (M+H).

Example 629

4-(6-(4-benzylpiperazin-1-yl)pyridine-3-yl)-6-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

The title compound was prepared (3.3 mg, 32% yield) according to themethod described for the synthesis of Example 628, replacing6-(2-methyloxazol-5-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride with6-(3-methylisoxazol-5-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 625). Following C18 reverse phasechromatography (0-60% ACN/water as the gradient eluent) the titlecompound was isolated cleanly (3.3 mg, 32% yield). MS (apci) m/z=476.2(M+H).

Example 630

4-(6-(4-(2-isopropoxyethyl)piperazin-1-yl)pyridin-3-yl)-6-(3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(3-methyl-1H-pyrazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 626; 10 mg, 0.026 mmol) in DMF (0.2 mL) was treated with TEA(18 μL, 0.13 mmol) and 2-(2-bromoethoxy)propane (8.7 mg, 0.052 mmol).The reaction mixture was stirred overnight at room temperature, then for4 h at 60° C. After cooling to room temperature, the reaction mixturewas purified directly by C18 reverse phase chromatography (0-60%ACN/water as the gradient eluent) to afford the title compound (3.4 mg,28% yield). MS (apci) m/z=471.2 (M+H).

Example 631

4-(6-(4-(2-isopropoxyethyl)piperazin-1-yl)pyridin-3-yl)-6-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(3-methylisoxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride (Example 625; 5 mg, 0.012 mmol) in dry DMA (0.2 mL) wastreated with TEA (16.5 μL, 0.12 mmol) and 2-(2-bromoethoxy)propane (6mg, 0.036 mmol). The reaction mixture was stirred overnight at 75° C.,and then additional TEA (7.2 μL, 0.052 mmol) and2-(2-bromoethoxy)propane (6 mg, 0.036 mmol) were added. The resultingmixture was stirred at 75° C. for 36 hr until the reaction was completeby LCMS. After cooling to room temperature, the reaction mixture waspurified directly by C18 reverse phase chromatography (20-80% ACN/wateras the gradient eluent) to afford the title compound (2 mg, 36% yield).MS (apci) m/z=472.2 (M+H).

Example 632

4-(6-(4-ethylpiperazin-1-yl)pyridine-3-yl)-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridin-3-carbonitrile

A room temperature solution of6-(2-methyloxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 624; 8 mg, 0.02 mmol) in DMF (0.2 mL) wastreated with DIEA (12.2 μL, 0.0698 mmol) and bromoethane (5 μL, 0.067mmol). The reaction mixture was stirred for 15 h at 50° C., and thenadditional DIEA (20 μL, 0.114 mmol) and bromoethane (5 μL, 0.067 mmol)were added. The resulting mixture was stirred for 4 d at 75° C. Aftercooling to room temperature, the reaction mixture was purified directlyby C18 reverse phase chromatography (5-70% ACN/water as the gradienteluent) to afford the title compound (3.2 mg, 44% yield). MS (apci)m/z=414.1 (M+H).

The compounds in Table FFF were prepared according to the methoddescribed for the synthesis of Example 632, replacing bromoethane withthe appropriate alkyl halide. Reactions were followed by LCMS, andreaction times, as well as additions of supplemental DIEA and alkylhalide were adjusted as necessary. Purifications were accomplished byC18 reverse phase chromatography using an appropriate gradient eluentallowing the clean isolation of the title compounds.

TABLE FFF MS (apci) Ex # Structure Chemical Name m/z 633

4-(6-(4-(2- ethoxyethyl)piperazin-1- yl)pyridin-3-yl)-6-(2-methyloxazol-5- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 458.2 (M + H)634

4-(6-(4-(2- isopropoxyethyl)piperazin- 1-yl)pyridin-3-yl)-6-(2-methyloxazol-5- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile MS (apci) m/z= 472.2 (M + H)

Example 635

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(3-methylisoxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride (Example 625; 6 mg, 0.014 mmol) in dry DMA (0.4 mL) wastreated with TEA (6 μL, 0.043 mmol), Me₄N(AcO)₃BH (7.5 mg, 0.028 mmol)and 6-methoxynicotinaldehyde (4 mg, 0.0284 mmol). The resulting mixturewas stirred overnight at room temperature, and then additional TEA (4μL, 0.22 mmol), Me₄N(AcO)₃BH (7.5 mg, 0.028 mmol) and6-methoxynicotinaldehyde (4 mg, 0.0284 mmol) were added. The reactionwas stirred at room temperature for 84 hr, then quenched with water andCHCl₃, and allowed to stir for 30 min at room temperature. The resultingmixture was filtered through a PS frit, and the organics were extractedwith EtOAc. The combined organic extracts were purified directly by C18reverse phase chromatography (20-80% ACN/water as the gradient eluent)to afford the title compound (1.3 mg, 18% yield). MS (apci) m/z=507.1(M+H).

Example 636

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(3-methyl-1H-pyrazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 626; 40 mg, 0.087 mmol) in DMF (0.4 mL) wastreated with TEA (61 μL, 0.44 mmol), 6-methoxynicotinaldehyde (36 mg,0.26 mmol) and Me₄N(AcO)₃BH (23 mg, 0.087 mmol). The resulting mixturewas stirred for 48 h at room temperature and then directly purified byC18 reverse phase chromatography (0-60% ACN/water as the gradienteluent) to afford the title compound (30 mg, 68% yield). MS (apci)m/z=506.2 (M+H).

The compounds in Table GGG were prepared according to the methoddescribed for the synthesis of Example 636, replacing6-(3-methyl-1H-pyrazol-5-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride and 6-methoxynicotinaldehyde with the appropriatepiperazine from Table DDD, and the appropriate commercial aldehyde.Reactions were followed by LCMS, and reaction times were adjusted asnecessary. In each example, title compounds were isolated cleanlyfollowing C18 reverse phase chromatography utilizing an appropriategradient eluent.

TABLE GGG MS (apci) Ex # Structure Chemical Name m/z 637

6-(1,5-dimethyl-1H-pyrazol- 3-yl)-4-(6-(4-((6- methoxypyridin-3-yl)methyl)piperazin-1- yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 520.2 (M + H) 638

6-(1,5-dimethyl-1H-pyrazol- 3-yl)-4-(6-(4-(pyrimidin-2-ylmethyl)piperazin-1- yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile 491.2 (M + H)

Example 639

4-(2-(4-benzylpiperazin-1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 281; 15 mg, 0.033 mmol) in DMF (0.2 mL) wastreated with (bromomethyl)benzene (8.4 mg, 0.049 mmol) and TEA (14 μL,0.098 mmol). The resulting mixture was stirred for 1 h at roomtemperature, then directly purified by C18 reverse phase chromatography(using 0-60% ACN/water as the gradient eluent) to afford the titlecompound (9.5 mg, 61% yield). MS (apci) m/z=476.2 (M+H).

Example 640

tert-butyl4-(6-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-3-yl)piperazine-1-carboxylate

A mixture of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 100 mg, 0.269 mmol),tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-carboxylate(131 mg, 0.269 mmol), Na₂CO₃ (143 mg, 1.35 mmol), and Pd(PPh₃)₄ (15.6mg, 0.0135 mmol) in 4:1 dioxane/water (4 mL) was sparged with Argon andthen stirred overnight at 90° C. After cooling to room temperature, thereaction mixture was concentrated in vacuo, and the residue waspartitioned between EtOAc and water. The aqueous extracts were washedwith EtOAc, and the combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica chromatography (eluted with a stepped gradient of 50-50%Hexanes/EtOAc followed by 25-75% Hexanes/EtOAc) to cleanly afford thetitle compound (13 mg, 10% yield). MS (apci) m/z=485.1 (M+H).

Example 641

6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(piperazin-1-yl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of tert-butyl4-(6-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridin-3-yl)piperazine-1-carboxylate(Example 640; 13 mg, 0.027 mmol) in DCM (4 mL) was treated with TFA (2mL, 0.4 mmol), and stirred for 4 h at room temperature. The reactionmixture was purified directly by reverse phase HPLC (5-95% water/ACNwith 0.1% TFA as the gradient eluent) to afford the title compound asthe TFA salt. The TFA salt was suspended in 4:1 DCM/iPrOH and washedwith saturated NaHCO₃. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to cleanly affordthe title compound (9 mg, 87% yield). MS (apci) m/z=385.1 (M+H).

Example 642

(R)-4-(5-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(5-(piperazin-1-yl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 641; 9 mg, 0.023 mmol) in DMF (4 mL) was treated withD-(−)-mandelic acid (5.34 mg, 0.351 mmol), HATU (8.90 mg, 0.023 mmol)and DIEA (40.8 μL, 0.234 mmol). The reaction was stirred for 16 h atroom temperature and then directly purified by silica chromatography(using a stepped gradient eluent of 100% EtOAc followed by 5% MeOH inEtOAc) to provide the title compound (3.2 mg, 26% yield). MS (apci)m/z=519.2 (M+H).

Example 643

(S)-(3-methoxypyrrolidin-1-yl)(4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)methanone

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (Example 312; 28.4 mg, 0.0657 mmol) and DIEA (114 μL,0.657) mmol) in DCM (500 μL) was added dropwise to a 0° C. solution oftriphosgene (7.80 mg, 0.0263 mmol) in DCM (273 μL). After stirring for 1h at 0° C., the reaction mixture was treated with(S)-3-methoxypyrrolidine hydrochloride (9.94 mg, 0.0723 mmol) and thenstirred for 16 h at room temperature. The resulting mixture was purifieddirectly by silica chromatography (40-100% DCM/acetone as the gradienteluent) to provide the title compound (13.5 mg, 42% yield). MS (apci)m/z=487.1 (M+H).

Example 644

3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

A room temperature solution of tert-butyl4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 325; 1.55 g, 3.13 mmol) in 1:1 DCM/TFA (15.0 mL) was stirredfor 30 min at room temperature, then concentrated in vacuo to afford thetitle compound as the TFA salt. The TFA salt was suspended in 4:1DCM/iPrOH and extracted with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica chromatography (1-30% DCM/MeOHwith 2% NH₄OH as the gradient eluent) to afford the title compound (716mg, 58% yield). MS (apci) m/z=494.2 (M+H), 495.2 (M+2), with Cl pattern.

Example 645

(S)-(4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)(3-methoxypyrrolidin-1-yl)methanone

A suspension of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridinedihydrochloride (Example 326; 14.1 mg, 0.0302 mmol) and DIEA (52.6 μL,0.302) mmol) in DCM (500 μL) was added dropwise to a 0° C. solution oftriphosgene (3.59 mg, 0.0121 mmol) in DCM (500 μL). After stirring for 1h at 0° C., the reaction mixture was treated with(S)-3-methoxypyrrolidine hydrochloride (4.57 mg, 0.0332 mmol) and thenstirred for 16 h at room temperature. The resulting mixture was dilutedwith DCM and washed with saturated NaHCO₃. The combined organic extractswere dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by silica chromatography (40-100% DCM/acetoneas the gradient eluent) to provide the title compound (7.2 mg, 46%yield). MS (apci) m/z=521.1 (M+H), 522.1 (M+2H).

Example 646

1-(4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-3-methylbutan-1-one

A room temperature solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 644; 51.7 mg, 0.131 mmol) in DCM (1.3 mL) was treatedsequentially with DIEA (45.7 μL, 0.263 mmol) and isovaleryl chloride(19.2 μL, 0.158 mmol). The reaction mixture was stirred for 16 h at roomtemperature and then directly purified by C18 reverse phasechromatography (5-95% water/ACN with 0.1% TFA as the gradient eluent) toafford the title compound as the TFA salt. The TFA salt was suspended in4:1 DCM/iPrOH and extracted with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to cleanly afford the title compound (48.9 mg, 78% yield). MS(apci) m/z=478.1 (M+H), 479.1 (M+2H).

Example 647

4-(6-(4-benzylpiperazin-1-yl)pyridine-3-yl)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

A room temperature solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine(Example 644; 52.3 mg, 0.133 mmol) in DCM (1.3 mL) was treatedsequentially with TEA (90.1 μL, 0.664 mmol) and benzyl bromide (47.3 μL,0.398 mmol). The resulting mixture was stirred for 16 h at roomtemperature and then directly purified by silica chromatography (1-25%DCM/MeOH with 2% NH₄OH as the gradient eluent) to afford the titlecompound (43.5 mg, 68% yield). MS (apci) m/z=484.1 (M+H), 485.1 (M+2H).

Example 648

1-(4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridine-2-yl)piperazin-1-yl)-3-methylbutan-2-ol

A room temperature solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 644; 52.6 mg, 0.134 mmol) in MeOH (1.3 mL) was treated with1,2-epoxy-3-methylbutane (13.8 mg, 0.160 mmol). The resulting mixturewas sealed and stirred for 16 h at 80° C. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo, and theresidue was purified by silica chromatography (1-25% DCM/MeOH with 2%NH₄OH as the gradient eluent) to afford the title compound (46.2 mg, 72%yield). MS (apci) m/z=480.2 (M+H), 481.2 (M+2), with Cl pattern.

Example 649

tert-butyl4-(5-(3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A cold (0° C.) solution of tert-butyl4-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yl)pyridine-2-yl)piperazine-1l-carboxylate(Example 311; 0.203 g, 0.442 mmol) in DMF (4 mL) was treated with NBS(0.0865 g, 0.486 mmol). After stirring for 1 h at room temperature, thereaction mixture was diluted with EtOAc and washed with brine. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (0-50% EtOAc in Hexanes as the gradient eluent) to affordthe title compound (0.157 g, 66% yield). MS (apci) m/z=538.0 (M+H).

Example 650

tert-butyl4-(5-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-4-yltrifluoromethanesulfonate (Intermediate 27; 250 mg, 0.694 mmol),tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl)piperazine-1-carboxylate(297 mg, 0.763 mmol), Na₂CO₃ (368 mg, 3.47 mmol), and Pd(PPh₃)₄ (40.1mg, 0.0347 mmol) in 4:1 dioxane/water (4 mL) was sparged with Argon for10 min, then stirred overnight at 90° C. under an Argon atmosphere.After cooling to room temperature, the reaction mixture was concentratedin vacuo, and the residue was partitioned between EtOAc and water. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (using 50-100% EtOAc in Hexanes as the gradient eluent)to cleanly afford the title compound (225 mg, 69% yield). MS (apci)m/z=485.1 (M+H). MS (apci) m/z=474.2 (M+H).

Example 651

3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

A room temperature solution of tert-butyl4-(5-(3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 650; 1.55 g, 3.13 mmol) in DCM (4.0 mL) was treated with TFA,then stirred overnight at room temperature. The reaction mixture wasconcentrated in vacuo and the residue was purified by reverse phase HPLC(5-95% water/ACN with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was suspended in 4:1DCM/iPrOH and washed with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford the title compound (151 mg, 79% yield). MS (apci)m/z=374.2 (M+H).

Example 652

(R)-2-hydroxy-1-(4-(5-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-phenylethan-1-one

A room temperature solution of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 651; 20 mg, 0.054 mmol) in DMF (4 mL) was treated withD-(−)-mandelic acid (12 mg, 0.080 mmol), HATU (20 mg, 0.054 mmol) andDIEA (93 μL, 0.54 mmol). The reaction was stirred for 16 h at roomtemperature, and then diluted with EtOAc and washed with water. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (using a stepped gradient of 25% Hexanes in EtOAcfollowed by 100% EtOAc) to provide the title compound (20 mg, 74%yield). MS (apci) m/z=508.2 (M+H).

Example 653

4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

A room temperature solution of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 651; 17 mg, 0.0455 mmol) in DMF (2 mL) was treated sequentiallywith benzyl bromide (17.3 μL, 0.0905 mmol) and TEA (31.7 μL, 0.146mmol). The reaction mixture was stirred overnight at room temperature,then diluted with EtOAc and washed with water. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica chromatography (using astepped gradient eluent of 25% Hexanes in EtOAc followed by 100% EtOAc)to cleanly afford the title compound (16 mg, 76% yield). MS (apci)m/z=464.2 (M+H).

Example 654

3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

A room temperature solution of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 651; 21 mg, 0.56 mmol) in DMF (2 mL) was treated sequentiallywith picolinaldehyde (0.021 g, 0.20 mmol), TEA (39 μL, 0.28 mmol) andNaBH(AcO)₃ (28.4 mg, 0.134 mmol). The resulting reaction mixture wasallowed to stir for 1 h at room temperature and then acetic acid (10 eq)was added. The reaction mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with EtOAc and washed withwater. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by reversephase HPLC (5-95% water/ACN with 0.1% TFA as the gradient eluent) toafford the title compound as the TFA salt. The TFA salt was suspended in4:1 DCM/iPrOH and washed with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford the title compound (20 mg, 77% yield) MS (apci)m/z=465.2 (M+H).

Example 655

tert-butyl4-(5-(6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A room temperature suspension of tert-butyl4-(5-(3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 649; 0.220 g, 0.409 mmol), potassium vinyltrifluoroborate (350mg, 1.23 mmol), Pd₂(dba)₃ (59.9 mg, 0.0654 mmol), XPhos (62.3 mg, 0.131mmol) and K₂CO₃ (169 mg, 1.23 mmol) in 4:1 dioxane/water (8 mL) wassparged with Argon and then stirred for 4 h at 90° C. under anatmosphere of Argon. After cooling to room temperature, the reactionmixture was concentrated in vacuo, then diluted with EtOAc and extractedwith water. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica chromatography (30-75% EtOAc in Hexanes as the gradient eluent)to afford the title compound (120 mg, 61% yield). MS (apci) m/z=486.1(M+H).

Example 656

tert-butyl4-(5-(3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A room temperature solution of tert-butyl4-(5-(6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 655; 0.120 g, 0.247 mmol) in EtOAc (6 mL) was treated with 10%Pd/C (0.0263 g, 0.0247 mmol), then sparged with H₂ for 10 min andstirred under an atmosphere of H₂ overnight at room temperature. Thereaction mixture was filtered through GF/F paper and the filtrate wasconcentrated in vacuo to afford the title compound (120 mg, quantitativeyield) in sufficient purity. MS (apci) m/z=488.1 (M+H).

Example 657

3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

A room temperature solution of tert-butyl4-(5-(3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 656; 0.120 g, 0.246 mmol) in DCM (4.0 mL) was treated with TFA(2 mL), then stirred for 4 h at room temperature. The reaction mixturewas concentrated in vacuo, and the residue was purified by reverse phaseHPLC (5-95% water/ACN with 0.1% TFA as the gradient eluent) to affordthe title compound as the TFA salt. The TFA salt was suspended in 4:1DCM/iPrOH and washed with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford the title compound (70 mg, 73% yield). MS (apci)m/z=388.2 (M+H).

Example 658

(R)-1-(4-(5-(3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)-2-hydroxy-2-phenylethanone

A room temperature solution of3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 657; 27 mg, 0.070 mmol) in DMF (4 mL) was treated withD-(−)-mandelic acid (16 mg, 0.10 mmol), HATU (26 mg, 0.070 mmol) andDIEA (121 μL, 0.70 mmol). The reaction was stirred 16 h at roomtemperature, and then diluted with EtOAc and washed with water. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silicachromatography (using a stepped gradient of 1:2 Hexanes in EtOAcfollowed by 1:4 Hexanes in EtOAc) to provide the title compound (20 mg,55% yield). MS (apci) m/z=522.2 (M+H).

Example 659

(S)-(4-(5-(3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazin-1-yl)(3-methoxypyrrolidin-1-yl)methanone

A suspension of3-ethyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 657; 38 mg, 0.098 mmol) and DIEA (102 μL, 0.59) mmol) inDriSolv® DCM (490 μL) was added dropwise to a 0° C. solution oftriphosgene (13 mg, 0.044 mmol) in DriSolv® DCM (490 μL). After stirringfor 30 min at 0° C., the reaction mixture was treated with(S)-3-methoxypyrrolidine hydrochloride (13 mg, 0.098 mmol), then stirredfor 48 h at room temperature. The resulting mixture was diluted withEtOAc and washed with water. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by reverse-phase HPLC (5-95% water/ACN with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The TFAsalt was suspended in 4:1 DCM/iPrOH and washed with saturated NaHCO₃.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to provide the title compound (30mg, 59% yield). MS (apci) m/z=515.2 (M+H).

Example 660

3-cyclopropyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

In a sealed vessel, a −35° C. solution of tert-butyl4-(5-(6-(1-methyl-1H-pyrazol-4-yl)-3-vinylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 655; 0.100 g, 0.206 mmol) in DCE (2 mL) was treatedsequentially with 1.0 M diethylzinc in Hexanes (4.12 mL, 4.12 mmol) anddiiodomethane (0.332 mL, 4.12 mmol). The resulting mixture was broughtto room temperature, and then stirred overnight at 75° C. The reactionmixture was diluted with DCM and washed with water. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford tert-butyl4-(5-(3-cyclopropyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate.The crude material was immediately suspended in 1:2 TFA/DCM (3 mL), andstirred for 30 min at room temperature. The reaction mixture wasconcentrated in vacuo and the residue was purified by reverse phase HPLC(5-95% water/ACN with 0.1% TFA as the gradient eluent) to afford thetitle compound as the TFA salt. The TFA salt was suspended in 4:1DCM/iPrOH and extracted with saturated NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford the title compound (1.1 mg, 1.3% yield). MS (apci)m/z=400.2 (M+H).

Example 661

(S)-4-(6-(4-(2-(dimethylamino)-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of(S)-4-(6-(4-(2-amino-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Example 50; 7 mg, 0.014 mmol) in anhydrousMeOH (0.4 mL) was treated sequentially with formaldehyde (20.3 □L, 0.27mmol) and Me₄N(AcO)₃BH (21.3 mg, 0.0811 mmol). The reaction mixture wasallowed to stir overnight at ambient temperature, before introducingadditional formaldehyde (5 □L, 0.066 mmol), and Me₄N(AcO)₃BH (5 mg,0.019 mmol). After stirring an additional period of 3 d at ambienttemperature, the mixture was quenched with water and CHCl₃, and thenextracted with CHCl₃ in a PS frit. The combined organic extracts wereconcentrated in vacuo, and the resulting residue was purified by C18reverse-phase chromatography (25-80% ACN in water as the gradienteluent) to afford the title compound (3 mg, 41% yield). MS (apci)m/z=546.3 (M+H).

Example 662

Isobutyl4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 50 mg, 0.11 mmol), isobutylcarbonochloridate (28 μL, 0.22 mmol), DMAP (1.3 mg, 0.011 mmol) and DIEA(98 □L, 0.55 mmol) in DCM (1.0 mL) was stirred overnight at ambienttemperature. The reaction mixture was washed with water, and the organicextracts were dried over anhydrous Na₂SO₄, filtered, concentrated invacuo. The resulting residue was purified by silica chromatography(0-20% acetone in DCM as the gradient eluent) to afford the titlecompound (4.2 mg, 8% yield). MS (apci) m/z=484.9 (M+H).

Example 663

(R)-4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)piperazine-1-carboxamide

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 34 mg 0.074 mmol) in anhydrous DMA (0.9 mL)was treated with (R)-1-fluoro-4-(1-isocyanatoethyl)benzene (14.7 mg,0.089 mmol) and TEA (52 □L, 0.37 mmol). While monitoring by LCMS, theresulting reaction mixture was stirred at ambient temperature untilcomplete. The mixture was directly purified by C18 reverse-phasechromatography (20-80% ACN/water with 0.1% formic acid) to afford thetitle compound (29.2 mg, 72% yield). MS (apci) m/z=550.3 (M+H).

Example 664

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(phenylsulfonyl)ethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 19.6 mg, 0.0429 mmol),((2-chloroethyl)sulfonyl)benzene (26.3 mg, 0.129 mmol) and TEA (59.7 μL,0.429 mmol) in dry DMA (500 μL) was stirred overnight at 75° C. Thereaction mixture was purified directly by C18 reverse-phasechromatography (20-80% ACN/Water as the gradient eluent) to afford thetitle compound (10.2 mg, 43% yield). MS (apci) m/z=553.2 (M+H).

Example 665

4-(6-(4-((6-(dimethylamino)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 0.125 g, 0.273 mmol) in dry DMA (500 μL) wastreated sequentially with TEA (40.7 μL, 0.292 mmol), Me₄N(AcO)₃BH (23.0mg, 0.0876 mmol), 6-(dimethylamino)nicotinaldehyde (13.2 mg, 0.0876mmol) and 1 drop of glacial acetic acid. After stirring overnight atambient temperature, the mixture was quenched with water/CHCl₃ andextracted with CHCl₃ in a PS frit. The combined organic extracts wereconcentrated in vacuo, and the residue was purified by C18 reverse-phasechromatography (20-80% ACN in water as the gradient eluent) to affordthe title compound (15 mg, 50% yield). MS (apci) m/z=519.2 (M+H).

Example 666

4-(6-(4-((5-fluoro-6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 100 mg, 0.219 mmol) in DCM (3 mL) wastreated with DIEA (95.5 μL, 0.547 mmol). After stirring for 5 min atambient temperature, the mixture was treated sequentially with5-fluoro-6-methoxynicotinaldehyde (37.3 mg, 0.241 mmol) and NaBH(AcO)₃(92.7 mg, 0.437 mmol). After stirring for 12 h at room temperature, thereaction mixture was diluted with DCM and washed with 10% Na₂CO_(3(aq)).The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silicachromatography (10% MeOH/DCM with 1% NH₄OH as the eluent) to afford thetitle compound (85 mg, 74% yield). MS (apci) m/z=524.2 (M+H).

Example 667

4-(6-(4-((5-chloro-6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 30 mg, 0.066 mmol) in DCM (1 mL) was treatedwith DIEA (29 μL, 0.16 mmol). After stirring for 5 min at ambienttemperature, the mixture was treated sequentially with3-chloro-5-formyl-2-methoxypyridine (17 mg, 0.098 mmol) and NaBH(AcO)₃(28 mg, 0.13 mmol). The resulting mixture was stirred for 12 h at roomtemperature, and then concentrated in vacuo. The residue was purified byC18 reverse-phase chromatography (5-95% ACN/water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The saltwas diluted with EtOAc, treated with saturated NaHCO_(3(aq)), andstirred for 10 min at ambient temperature. The organic extracts wereseparated, dried over anhydrous MgSO₄, filtered, and concentrated invacuo to cleanly afford the title compound (29 mg, 82% yield). MS (apci)m/z=540.2 (M+H).

The compounds in Table HHH were prepared and purified according themethod described for the synthesis of Example 667, replacing3-chloro-5-formyl-2-methoxypyridine with the appropriate aldehydestarting material.

TABLE HHH MS apci Ex # Structure Chemical Name (m/z) 668

4-(6-(4-((6- ethoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 520.3 (M + H) 669

4-(6-(4-((6- isopropoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 534.3 (M + H) 670

4-(6-(4-((5,6- dimethoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 536.2 (M + H) 671

4-(6-(4-((2,6- dimethoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 536.3 (M + H) 672

4-(6-(4-((6-methoxy-4- methylpyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 520.2 (M + H) 673

4-(6-(4-((6-ethoxy-5- fluoropyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 538.3 (M + H) 674

6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(4- ((6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)methyl)piperazin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 574.2 (M + H) 675

4-(6-(4-((6- (difluoromethoxy) pyridin-3-yl) methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 542.2 (M + H) 676

4-(6-(4-((6-methoxy-5- methylpyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 520.2 (M + H) 677

6-(1-methyl-1H- pyrazol-4-yl)-4-(6-(4- ((6-(trifluoromethyl)pyridin-3-yl)methyl) piperazin-1-yl) pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 544.2 (M + H) 678

4-(6-(4-((6-methoxy-2- methylpyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 520.3 (M + H) 679

4-(6-(4-((6-(tert- butyl)pyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 532.3 (M + H) 680

4-(6-(4-((6-(2- hydroxypropan-2- yl)pyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 534.3 (M + H) 681

4-(6-(4-((6- cyanopyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 501.2 (M + H)

Example 682

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 50 mg, 0.109 mmol) in DMF (1093 μL) wastreated with 1-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde (22.5 mg,0.164 mmol) and TEA (45.7 μL, 0.328 mmol). The mixture was acidified toabout pH 6 with AcOH, and then stirred for 1 h at ambient temperature.The reaction mixture was treated with NaBH₃CN (10.3 mg, 0.164 mmol), andstirred for 2 d at ambient temperature. The resulting suspension waswarmed to dissolve particulates, and directly purified by C18reverse-phase chromatography (5-60% ACN/water as the gradient eluent) toafford the title compound together with impurities. Additionalpurification by C18 reverse-phase chromatography (5-45% ACN/water with0.1% HCl_((aq)) as the gradient eluent) cleanly afforded the titlecompound as the dihydrochloride salt (11.2 mg, 19% yield). MS (apci)m/z=506.2 (M+H).

Example 683

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A suspension of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 50 mg, 0.109 mmol) in DMF (1093 μL) wastreated with 1-methyl-2-oxo-1,2-dihydropyridine-4-carbaldehyde (22.5 mg,0.164 mmol) and TEA (45.7 μL, 0.328 mmol). The mixture was acidified toabout pH 6 with AcOH, and then stirred for 2 h at ambient temperature.The reaction mixture was treated with NaBH₃CN (10.3 mg, 0.164 mmol), andstirred for 2 d at ambient temperature. The resulting suspension waswarmed to dissolve particulates, and directly purified by C18reverse-phase chromatography (5-50% ACN/water as the gradient eluent) toafford semi pure title compound. Additional purification, of this semipure material, by C18 reverse-phase chromatography (5-50% ACN/water with0.1% HCl_((aq)) as the gradient eluent) cleanly afforded the titlecompound as the dihydrochloride salt (20.2 mg, 32% yield). MS (apci)m/z=506.2 (M+H).

Example 684

(S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((tetrahydro-2H-pyran-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of (S)-(tetrahydro-2H-pyran-2-yl)methyl4-methylbenzenesulfonate

a mixture of (s)-(tetrahydro-2h-pyran-2-yl)methanol (1 g, 8.61 mmol),sulfur (0.276 g, 8.61 mmol), TsCl (1.81 g, 9.47 mmol), and KOH(s) (0.725g, 12.9 mmol) in THF (10 mL) was stirred overnight at ambienttemperature. The resulting suspension was filtered through a glass frit,rinsing with THF. The filtrate was concentrated in vacuo, and theresulting residue was purified by silica chromatography (100% DCM aseluent) to afford the title compound (1.33 g, 57% yield). ¹H NMR (CDCl₃)δ 7.79 (d, 2H), 7.33 (d, 2H), 3.95 (d, 2H), 3.91-3.96 (m, 1H), 3.50-3.56(m, 1H), 3.34-3.40 (m, 1H), 2.44 (s, 3H), 1.82-1.86 (m, 1H), 1.41-1.59(m, 4H), 1.22-1.31 (m, 1H).

Step 2: Preparation of(S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-((tetrahydro-2H-pyran-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 2; 50 mg, 0.109 mmol),(S)-(tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (Step 1;35.5 mg, 0.131 mmol) and TEA (76.2 μL, 0.547 mmol) was dissolved in 1:1DCM:DMA (2 mL). After stirring overnight at 90° C., additional(S)-(tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (Step 1;35.5 mg, 0.131 mmol) and a drop of TEA were added and reaction wasstirred for another day to reach completion. The crude mixture wasdirectly purified by reverse-phase chromatography (5-50% ACN/water) toafford the title compound (26.5 mg, 50% yield). MS (apci) m/z=483.2(M+H).

Example 685

4-(6-(4-((6-methoxypyridin-3-yl)methyl)-2-oxopiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-(5-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate

A mixture of 5-bromo-2-fluoropyridine (0.175 mL, 1.70 mmol), tert-butyl3-oxopiperazine-1-carboxylate (0.512 g, 2.56 mmol) and potassiumt-butoxide (0.287 g, 2.56 mmol) in toluene (17.0 mL) was refluxedovernight. After cooling to ambient temperature, the mixture wasextracted with EtOAc and water. The organic extracts were washed withbrine, then dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude residue (607 mg, quantitative yield) was carriedforward without further purification.

Step 2: Preparation of 1-(5-bromopyridin-2-yl)piperazin-2-one

A mixture of tert-butyl4-(5-bromopyridin-2-yl)-3-oxopiperazine-1-carboxylate (607 mg, 1.70mmol) in TFA (8 mL, 1.70 mmol) and DCM (8.52 mL) was stirred for 30 minat ambient temperature. The reaction mixture was concentrated in vacuo.The resulting residue was purified by silica chromatography (5-95%Hexanes:EtOAc as the gradient eluent) to afford the title compound (208mg, 48% yield). MS (apci) m/z=258.0 (M+2), with bromine isotopic ratio.

Step 3: Preparation of1-(5-bromopyridin-2-yl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-2-one

A mixture of 1-(5-bromopyridin-2-yl)piperazin-2-one (208 mg, 0.812 mmol)and 6-methoxynicotinaldehyde (0.134 g, 0.975 mmol) in DCE (8.12 mL) wasstirred for 10 min at ambient temperature, and then NaBH(AcO)₃ (0.344 g,1.62 mmol) was added. The resulting mixture was stirred for anadditional 2 h at ambient temperature before extracting with DCM andwater. The aqueous extracts were back-extracted with additional DCM. Thecombined DCM extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by silica chromatography (5-95% EtOAc:Hexanes as the gradienteluent) to afford the title compound (274 mg, 89% yield). MS (apci)m/z=377.0 (M+), 379.1 (M+2), with bromine isotopic ratio.

Step 4: Preparation of4-((6-methoxypyridin-3-yl)methyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-2-one

A mixture of1-(5-bromopyridin-2-yl)-4-((6-methoxypyridin-3-yl)methyl)piperazin-2-one(274 mg, 0.726 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (738 mg,2.91 mmol), KOAc (143 mg, 1.45 mmol) and PdCl₂(dppf).CH₂Cl₂ (59.3 mg,0.0726 mmol) in dioxane (7.26 mL) was stirred overnight at 90° C. Aftercooling to ambient temperature, the reaction mixture was filteredthrough GF/F paper. The filtrate was concentrated in vacuo, and theresulting residue was purified by silica chromatography (5-95%Hexanes:EtOAc as the gradient eluent) to afford the title compound (60mg, 20% yield). MS (apci) m/z=425.2 (M+H).

Step 5: Preparation of4-(6-(4-((6-methoxypyridin-3-yl)methyl)-2-oxopiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 45 mg, 0.12 mmol)4-((6-methoxypyridin-3-yl)methyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-2-one(62 mg, 0.15 mmol), Pd₂(dba)₃ (5.6 mg, 0.0061 mmol), X-Phos (12 mg,0.024 mmol) and 2 M Na₂CO_(3(aq)) (0.15 mL, 0.303 mmol) in dioxane (0.61mL) was degassed with Ar for 5 min. The mixture was stirred for 3 h at90° C. After cooling to ambient temperature, the reaction mixture wasfiltered through GF/F paper and then concentrated in vacuo. The residuewas purified by C18 reverse-phase chromatography (5-95% ACN/watercontaining 0.1% TFA) to afford the title compound as a TFA salt (27 mg).The TFA salt was partitioned between DCM and saturated Na₂CO_(3(aq)).The organic extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to cleanly afford the titlecompound (20.4 mg, 32% yield). MS (apci) m/z=520.2 (M+H).

Example 686

4-(6-(2-benzyl-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a microwave vessel, a room temperature mixture of4-(6-Fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 30 mg, 0.094 mmol) and2-benzylhexahydroimidazo[1,5-a]pyrazin-3(2H)-one (44 mg, 0.19 mmol) inDMSO (471 μL) was subjected to microwave irradiation for 28 h at 150° C.The reaction mixture was cooled to room temperature, and then purifieddirectly by C18 reverse-phase chromatography (5-60% ACN/water as thegradient eluent) to afford the title compound (8.1 mg, 15% yield). MS(apci) m/z=530.2 (M+H).

Example 687

4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

At ambient temperature, a mixture of4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 486; 21 mg, 0.053 mmol), 2-methoxy-5-pyridinecarboxylic acid(12.2 mg, 0.0795 mmol) and HATU (22.2 mg, 0.0583 mmol) in DCM (530 μL)was treated with DIEA (46.3 μL, 0.265 mmol). The resulting mixture wasstirred for 1 h at ambient temperature before concentrating in vacuo.The crude residue was purified by C18 reverse-phase chromatography(5-95% ACN/water containing 0.1% TFA as the gradient eluent) to affordthe title compound as the TFA salt. The TFA salt was partitioned betweenDCM and saturated NaHCO_(3(aq)). The DCM extracts were reserved and theaqueous extracts were back-extracted with DCM. The DCM extracts werecombined, washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to cleanly afford the title compound (19.1 mg, 68%yield). MS (apci) m/z=532.2 (M+H).

The compounds in the Table III were prepared, purified and free-based ina similar fashion as described for the synthesis of Example 687,replacing 2-methoxy-5-pyridinecarboxylic acid with the appropriatecarboxylic acid starting material. Reaction progression in each examplewas followed by LCMS, and reaction times were adjusted as necessary.

TABLE III MS apci Ex # Structure Chemical Name (m/z) 688

4-(6-(6-(5-fluoro-6- methoxynicotinoyl)- 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 550.2 (M + H) 689

4-(6-(6-(3-fluoro-4- methoxybenzoyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)- 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile 549.2 (M + H) 690

4-(6-(6-(3-chloro-4- methoxybenzoyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 565.2 (M + H) 691

4-(6-(6-(2-(5- fluoropyridin-2- yl)acetyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3- yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile 534.2 (M + H)

Example 692

4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A solution of4-(6-Fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P6; 0.10 g, 0.31 mmol) in DMSO (5 mL) was treated withtert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (69 mg, 0.35mmol) and K₂CO₃ (0.22 g, 1.6 mmol). The resulting mixture was stirredovernight at 90° C. before introducing additional tert-butyl3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (70 mg, 0.36 mmol) andK₂CO₃ (0.1 g, 0.73 mmol). The reaction mixture was stirred for anadditional 24 h at 90° C. After cooling to ambient temperature, thereaction mixture was diluted with EtOAc (10 mL), and washed with water.The combined organic extracts were dried over anhydrous Na₂SO₄, thenfiltered and concentrated in vacuo. The isolated solids were dissolvedin DCM (2.5 mL), treated with 5M HCl in iPrOH, (0.3 mL) and stirredovernight at ambient temperature. Concentration of the reaction mixturein vacuo afforded the title compound as the dihydrochloride salt, whichwas used directly in the next step without further purification (133.7mg, 89% yield). MS (apci) m/z=397.2 (M+H).

Step 2: Preparation of4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Step 1; 26 mg, 0.055 mmol) in DMA (1 mL) was treatedwith TEA (23.2 μL, 0.166 mmol), NaBH(AcO)₃ (17.6 mg, 0.0831 mmol) and6-methoxynicotinaldehyde (11.4 mg, 0.0831 mmol). The resulting mixturewas stirred for 2 d at room temperature, before quenching with water.The mixture was extracted with DCM, and the combined organic extractswere dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The crude residue was purified by C18 reverse-phase chromatography(20-80% ACN/water as the gradient) to afford the title compound (5.3 mg,19% yield). MS (apci) m/z=518.2 (M+H).

Example 693

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-(pyridin-2-ylmethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Following a similar method to that used in Step 2 for the preparationand purification of Example 692, replacing 6-methoxynicotinaldehyde withpicolinaldehyde, the title compound was isolated cleanly (7.4 mg, 26%yield). MS (apci) m/z=488.2 (M+H).

Example 694

4-(6-(6-(2-ethoxyethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 692, Step 1; 20 mg, 0.0426 mmol) in DMA (500μL) was treated with TEA (59.4 μL, 0.426 mmol), and1-bromo-2-ethoxyethane (16.1 μL, 0.128 mmol). The resulting mixture wasstirred overnight at 75° C., then cooled to ambient temperature anddirectly purified by C18 reverse-phase chromatography (20-80% ACN/wateras the gradient eluent) to afford the title compound (2 mg, 10% yield).MS (apci) m/z=469.2 (M+H).

Example 695

6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(6-propyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 692, Step 1; 20 mg, 0.0426 mmol) in DMA (500μL) was treated with TEA (5.94 μL, 0.0426 mmol), and 1-iodopropane (7.24mg, 0.0426 mmol). The resulting mixture was stirred overnight at ambienttemperature, and then directly purified by C18 reverse-phasechromatography (20-80% ACN/water as the gradient eluent) to afford thetitle compound (2 mg, 10% yield). MS (apci) m/z=439.2 (M+H).

Example 696

6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 266; 21 mg, 0.043 mmol) in DMA (0.5 mL) wastreated with TEA (17.8 μL, 0.128 mmol), Me₄N(AcO)₃BH (16.8 mg, 0.0638mmol) and 6-methoxynicotinaldehyde (7 mg, 0.05 mmol). The resultingmixture was stirred overnight at room temperature before introducingadditional TEA (20 μL, 0.144 mmol), Me₄N(AcO)₃BH (10 mg, 0.038 mmol) and6-methoxynicotinaldehyde (7.01 mg, 0.0511 mmol). The reaction mixturewas stirred for an additional period of 3 d prior and then quenched withwater/CHCl₃. The quenched mixture was extracted with CHCl₃ in a PS Frit,and the combined organic extracts were concentrated in vacuo. The cruderesidue was purified by C18 reverse-phase chromatography (20-80%ACN/water as the gradient eluent) to afford the title compound (6.9 mg,30% yield). MS (apci) m/z=519.2 (M+H).

Example 697

6-(1-isopropyl-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of 1-amino-3,5-dibromopyridin-1-ium2,4,6-trimethylbenzenesulfonate

To a solution of O-(mesitylsulfonyl)hydroxylamine (Intermediate R1; 409g, 1.90 mol) in DCM (2 L) was added a solution of 3,5-dibromopyridine(320 g, 1.35 mol) in DCM (2.5 L) at 0-5° C. The reaction was stirred for16 h at this temperature before ether (5 L) was added at 0-5° C. Thesuspension was filtered and the filter cake was washed with Et₂O (4 L)to give the title product (500 g, 82% yield), which was directly usedfor the next step without further purifications. ¹H NMR (d⁶-DMSO) □ 9.11(s, 2H), 8.92 (s, 1H), 8.73 (s, 2H), 6.75 (s, 2H), 2.50 (s, 3H), 2.17(s, 3H).

Step 2: Preparation of 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile

To a mixture of 1-amino-3,5-dibromopyridin-1-ium2,4,6-trimethylbenzenesulfonate (40 g, 88.5 mmol) in dioxane (400 mL)was added acrylonitrile (10.72 g, 202 mmol) and DIEA (14.8 g, 11.5mmol), then stirred at ambient temperature for 3 h.2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (41.8 g, 184 mmol) was addedto the reaction mixture and stirred at ambient temperature for 3 hrs.The reaction mixture was poured into water (1.6 L), filtered, and theresulting solid was purified by silica chromatography(eluent=EtOAc/Petroleum ether 1:2) to afford the title product as whitesolid (13.8 g, 52% yield). ¹H NMR (CDCl₃) □ 8.69 (d, J=1.4 Hz, 1H), 8.28(s, 1H), 7.73 (d, J=1.4 Hz, 1H).

Step 3: Preparation of1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine

A cold (0° C.) solution of1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(20.00 g, 69.16 mmol), 6-methoxynicotinaldehyde (10.43 g, 76.08 mmol),and acetic acid (0.40 mL, 6.916 mmol) in anhydrous DCM (350 mL) wastreated with NaBH(OAc)₃ (21.99 g, 103.7 mmol), added in 2 portionsapproximately 1 min apart. The resulting mixture was stirred overnightat ambient temperature. The reaction mixture was quenched with theaddition of silica gel (40 g) and Celite® (40 g). The quenched mixturewas stirred for 5 min at ambient temperature before activated charcoal(20 g) was introduced. After stirring for 10 min at ambient temperature,the mixture was filtered through a silica gel plug (100 g) topped withCelite® and the plug was rinsed with a solution of 70% acetone in DCM(5×250 mL). The resultant filtrate was concentrated in vacuo. The cruderesidue was diluted with heptane (80 mL), and the solution was slowlytreated with saturated NaHCO_(3(aq)) (300 mL). The biphasic suspensionwas cooled in an ice bath to an internal temperature of 10° C., andsubsequently vacuum filtered, rinsing the filter cake with minimal coolwater and cool heptane. The filter cake was dissolved in MTBE,concentrated in vacuo, and dried in a vacuum oven to cleanly afford thetitle compound (20.66 g, 73% yield). MS (apci) m/z=411.2 (M+H).

Step 4: Preparation of6-bromo-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile (55 mg,0.18 mmol),1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(67 mg, 0.16 mmol), Pd(PPh₃)₄ (5.3 mg, 0.0046 mmol) and 2 MNa₂CO_(3(aq)) (15 μL, 135 mmol) in DMF (1.8 mL) was stirred overnight at60° C. After cooling to ambient temperature, the reaction mixture wasdirectly purified by silica chromatography (1-10% DCM:MeOH as theeluent) to afford the title compound (79 mg, 86% yield). MS (apci)m/z=505.1 (M+1). ¹H NMR showed 7:1 selectivity. ¹H NMR (400 MHz,CDCl₃-d) □□ 8.68 (d, 1H), 8.32 (d, 1H), 8.25 (s, 1H), 8.08 (d, 1H), 7.68(dd, 1H), 7.62 (dd, 1H), 7.37 (d, 1H), 6.74 (d, 2H), 3.94 (s, 3H), 3.65(t, 4H), 3.49 (s, 2H), 2.55 (t, 4H).

Step 5: Preparation of6-(1-isopropyl-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of6-bromo-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(24 mg, 0.0476 mmol),1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(13.5 mg, 0.0571 mmol), Pd(PPh₃)₄ (1.37 mg, 0.00119 mmol) and 2 MNa₂CO_(3(aq)) (59.5 μL, 0.119 mmol) in dioxane (476 μL) was stirredovernight at 90° C. After cooling to ambient temperature, the reactionmixture was directly purified by C18 reverse-phase chromatography (5-95%water/ACN with 1% TFA as the gradient eluent) to afford the titlecompound as the TFA salt. The TFA salt was partitioned between DCM andsaturated NaHCO_(3(aq)). After back-extracting the aqueous layer withDCM, the combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to cleanly affordthe title compound (15.7 mg, 62% yield). MS (apci) m/z=534.4 (M+H).

Example 698

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(6-(piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

A solution of6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 590; 250 mg, 0.510 mmol) in TFA (10.2 mL, 5.10 mmol) wasstirred overnight at 65° C. After cooling to ambient temperature, themixture was concentrated in vacuo to afford the title compound (288 mg,94% yield), which was used in the next step without further purificationor analysis.

Step 2: Preparation of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (288 mg, 0.481 mmol) in dry DMA (3 mL) wastreated with TEA (213 μL, 1.53 mmol), Me₄N(AcO)₃BH (201 mg, 0.765 mmol)and 6-methoxynicotinaldehyde (84.0 mg, 0.612 mmol). The mixture wasstirred overnight at room temperature and then quenched with water andCHCl₃. The mixture was extracted with CHCl₃, and the combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The crude residue was first purified by C18 reverse-phasechromatography using 15-50% ACN/water with 1% HCl as the gradient eluentand then purified by C18 reverse-phase chromatography using 5-50ACN/water with 0.1% formic acid as the gradient eluent to afford thetitle compound (40 mg, 16% yield). MS (apci) m/z=492.2 (M+H).

Example 699

4-(6-(4-((6-methoxypyridin-2-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A room temperature solution of4-(6-(piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) (Example 698, Step 1; 6 mg, 0.0162 mmol) indry DMA (900 μL) was treated sequentially with TEA (22.6 μL, 0.162 mmol)and 2-(bromomethyl)-6-methoxypyridine (9.82 mg, 0.0486 mmol). Thereaction mixture was stirred overnight at room temperature beforeintroducing additional TEA (1 μL, 0.01 mmol) and2-(bromomethyl)-6-methoxypyridine (2 mg, 0.01 mmol). The reactionmixture was stirred at room temperature until LCMS indicated thereaction was complete. The reaction mixture was directly purified by C18reverse-phase chromatography (15-80% ACN/water with 0.1% formic acid asthe gradient eluent) to cleanly afford the title compound (2.5 mg, 51%yield). MS (apci) m/z=492.2 (M+H).

Example 700

(R)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 698; Step 2; 18 mg, 0.0366 mmol) in 2-methoxyethanol (1 mL) wastreated sequentially with Cs₂CO₃ (40 mg, 0.123 mmol) and(R)-2-methyloxirane (7.7 μL, 0.110 mmol). The mixture was stirred for 40h at 75° C. After cooling to ambient temperature, the mixture wasfiltered to remove the inorganic material (Cs₂CO₃), and the filtrate wasdirectly purified by C18 reverse-phase chromatography (10-80% ACN/waterwith 0.1% formic acid as the gradient eluent) to afford the titlecompound (13 mg, 65% yield). MS (apci) m/z=550.3 (M+H).

Example 701

(S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 698; Step 2; 23 mg, 0.0468 mmol) in 2-methoxyethanol (500 μL)was treated sequentially with Cs₂CO₃ (45.7 mg, 0.140 mmol) and(S)-2-methyloxirane (8.2 mg, 0.140 mmol). The resulting mixture wasstirred at 75° C. and monitored for completion by LCMS. Upon completionthe reaction mixture was cooled to ambient temperature, then dilutedwith DCM and quenched with saturated NH₄Cl_((aq)). The biphasic mixturewas extracted with DCM, and the combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by C18 reverse-phase chromatography (10-70%ACN/water with 0.1% formic acid as the gradient eluent) to afford thetitle compound (14.6 mg, 57% yield). MS (apci) m/z=550.3 (M+H).

Example 702

6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 698; Step 2; 11.8 mg, 0.02401 mmol) in dry DMA (500 μL) wastreated sequentially with Cs₂CO₃ (78.2 mg, 0.240 mmol) and1-chloro-2-methylpropan-2-ol (12.3 μL, 0.110 mmol). The resultingmixture was stirred overnight at ambient temperature before introducingadditional 1-chloro-2-methylpropan-2-ol (12 μL, 0.110 mmol). Afterstirring for 24 h at ambient temperature, additional1-chloro-2-methylpropan-2-ol (12.3 μL, 0.110 mmol) was introduced, andthe reaction was monitored for completion by LCMS. Upon completion, thereaction mixture was quenched with water/CHCl₃, and the biphasic mixturewas extracted with CHCl₃ in a PS Frit. The combined organic extractswere concentrated in vacuo, and the crude residue was purified by C18reverse-phase chromatography (15-80% ACN/water with 0.1% formic acid asthe gradient eluent) to afford the title compound (1.9 mg, 14% yield).MS (apci) m/z=564.3 (M+H).

Example 703

6-(1-(2-(isopropylsulfonyl)ethyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 698; Step 2; 23 mg, 0.047 mmol) in dry DMA (500 μL) was treatedsequentially with Cs₂CO₃ (91 mg, 0.28 mmol) and2-((2-chloroethyl)sulfonyl)propane (24 mg, 0.14 mmol). The resultingmixture was stirred overnight at 60° C. After cooling to ambienttemperature, the reaction mixture was diluted with CHCl₃ and quenchedwith saturated NH₄Cl_((aq)). The resulting biphasic mixture wasextracted with CHCl₃ in a PS Frit. The combined organic extracts thenwere concentrated in vacuo, and the crude residue was purified by C18reverse-phase chromatography (10-70% ACN/water with 0.1% formic acid asthe gradient eluent) to afford the title compound (14 mg, 48% yield). MS(apci) m/z=626.3 (M+H).

The compounds in Table JJJ were prepared using a similar method to thatdescribed for the synthesis of Example 703, replacing2-((2-chloroethyl)sulfonyl)propane with the appropriate alkyl halidestarting material and using temperatures ranging from 60° C.-75° C.Reaction progression in each example was monitored by LCMS, and reactiontimes were adjusted as necessary. Upon completion, reactions werequenched using CHCl₃ and either water or saturated NH₄Cl_((aq)), thenworked up and purified using a method similar to that described inExample 703 using the appropriate gradient eluent in C18 reverse-phasechromatographic purification.

TABLE JJJ MS apci Ex # Structure Chemical Name (m/z) 704

6-(1-(2- isopropoxyethyl)-1H- pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin-1- yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 578.4 (M + H) 705

4-(6-(4-((6- methoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1- (tetrahydro-2H-pyran- 4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 576.4 (M + H) 706

3-(4-(3-cyano-4-(6-(4- ((6-methoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a] pyridin-6-yl)-1H- pyrazol-1-yl)-N,N-dimethylpropanamide 591.3 (M + H) 707

(R)-6-(1-(3-hydroxy-2- methylpropyl)-1H- pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 564.3 (M + H) 708

(S)-6-(1-(3-hydroxy-2- methylpropyl)-1H- pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3- yl)methyl)piperazin- 1-yl)pyridin-3-yl)pyrazolo[1,5-a] pyridine-3- carbonitrile 564.3 (M + H) 709

6-(1-(2- methoxypropyl)-1H- pyrazol-4-yl)-4-(6-(4- ((6-methoxypyridin-3-yl)methyl)piperazin- 1-yl)pyridin-3- yl)pyrazolo[1,5-a] pyridine-3-carbonitrile 564.3 (M + H) 710

2-(4-(3-cyano-4-(6-(4- ((6-methoxypyridin-3- yl)methyl)piperazin-1-yl)pyridin-3- yl)pyrazolo[1,5-a] pyridin-6-yl)-1H- pyrazol-1-yl)-N,N-dimethylacetamide 577.3 (M + H)

Example 711

6-(1-(azetidin-3-vi)-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)-piperazin-1)pyridin-3-yl)pyrazolo[1.5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) Step 1: Preparation of tert-butyl3-(4-(3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

A solution of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 698; Step 2; 60 mg, 0.12 mmol) in DMA (1 mL) was treatedsequentially with Cs₂CO₃ (240 mg, 0.73 mmol) and tert-butyl3-iodoazetidine-1-carboxylate (100 mg, 0.370 mmol). The resultingmixture was stirred for 4 h at 60° C. After cooling to ambienttemperature, the reaction mixture was quenched with saturatedNH₄Cl_((aq)). The resulting biphasic mixture was extracted with CHCl₃.The combined organic extracts were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude residue was purified by silicachromatography (0-15% MeOH/EtOAc as the gradient eluent) to afford thetitle compound (70 mg, 89% yield). MS (apci) m/z=647.3 (M+H).

Step 2: Preparation of6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

A suspension of tert-butyl3-(4-(3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(Step 1; 70 mg, 0.11 mmol) in DCM (1 mL) was treated with 5 M HCl iniPrOH (110 μL, 0.54 mmol). The resulting suspension was stirredovernight at ambient temperature. The mixture was solubilized using 1 MHCl_((aq)) and adjusted to pH 7 using 1 M NaOH_((aq)). The biphasicmixture was extracted with DCM, and the combined organic extracts weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by C18 reverse-phase chromatography (5-95%ACN/water with 0.1% TFA as the gradient eluent) to cleanly afford thetitle compound (4.4 mg, 7% yield). MS (apci) m/z=547.3 (M+H).

Example 712

tert-butyl4-(4-(3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 698; Step 2; 0.070 g, 0.142 mmol) and Cs₂CO₃ (0.199 g, 0.610mmol) in DMA (1 mL) was treated sequentially with tert-butyl4-bromopiperidine-1-carboxylate (113 mg, 0.427 mmol). The resultingmixture was stirred overnight at 75° C. before introducing additionalCs₂CO₃ (278 mg, 0.142 mmol) and tert-butyl4-bromopiperidine-1-carboxylate (38 mg, 0.142 mmol). The resultingmixture was stirred for 3 h at 75° C. After cooling to ambienttemperature, the reaction mixture was diluted with DCM, and quenchedwith saturated NH₄Cl_((aq)). The resulting biphasic mixture wasextracted with DCM. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica chromatography (0-10% MeOH/EtOAc as the gradienteluent) to afford the title compound (113 mg, quantitative yield). MS(apci) m/z=675.3 (M+H).

Example 713

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl4-(4-(3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Example 712; 113 mg, 0.167 mmol) in DCM (1 mL) was treated with 5 M HClin iPrOH (200 μL, 0.837 mmol). The resulting mixture was stirred for 2 hat ambient temperature, before concentrating in vacuo. The residue wassolubilized using 1 M HCl_((aq)), and then treated with 1 M NaOH_((aq)).The resulting suspension was concentrated in vacuo, and the cruderesidue was purified by C18 reverse-phase chromatography (10-70%ACN/water with 0.1% formic acid as the gradient eluent) to cleanlyafford the title compound (42.3 mg, 52% yield). MS (apci) m/z=575.3(M+H).

Example 714

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

A solution of tert-butyl4-(4-(3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Example 712; 8 mg, 0.01 mmol) in Formic acid (89.4 μL, 2.37 mmol) andformaldehyde (35.6 μL, 0.474 mmol) was sealed and stirred for 4 h at 90°C. After cooling to ambient temperature, the reaction mixture wasconcentrated in vacuo then purified by C18 reverse-phase chromatography(5-95% ACN/water with 0.1% TFA as the gradient eluent) to cleanly affordthe title compound as the bis-TFA salt (3.8 mg, 54% yield). MS (apci)m/z=589.3 (M+H).

Example 715

(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidinehydrochloride

Cold (0° C.) TFA (2 mL) was added to tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(1.5 g, 4.0 mmol), and the mixture was stirred for 10 min at ambienttemperature. The mixture was concentrated in vacuo, and the resultingresidue was treated with 4N HCl in dioxane (5 mL). The reaction mixturewas concentrated in vacuo, azeotroping with ACN, and then dried underhigh vacuum to cleanly afford the title compound (1.7 g, quantitativeyield). MS (apci) m/z=278.2 (M+H).

Step 2: Preparation of1-(2-methoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine

At ambient temperature, a solution4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidinehydrochloride (Step 1; 1.5 g, 4.8 mmol) in DMF (19 mL) was treatedsequentially with K₂CO₃ (2.3 g, 17 mmol) and 1-bromo-2-methoxyethane(1.1 mL, 12 mmol). The resulting mixture was stirred for 3 h at 70° C.,then overnight at ambient temperature. The reaction mixture wasfiltered, and the filtrate was concentrated in vacuo. The resultingresidue was suspended in 5% iPrOH/DCM (100 mL), and stirred for 5-10 minat ambient temperature. The mixture was filtered through GF/F paper, andthe filtrate was concentrated and dried in vacuo. The resulting residuewas triturated with hexanes (5 mL) to afford the title compound (2.43 g,quantitative yield). MS (apci) m/z=336.2 (M+H).

Step 3: Preparation of tert-butyl4-(5-(3-cyano-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube, a mixture of tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P14; 100 mg, 0.181 mmol),1-(2-methoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine(60.7 mg, 0.181 mmol), Pd₂(dba)₃.CHCl₃ (9.37 mg, 0.00905 mmol), XPhos(17.3 mg, 0.0362 mmol) and K₂CO_(3(s)) (75.0 mg, 0.543 mmol) in 4:1dioxane/water (1.81 mL) was sparged for 5 min with N_(2(g)), and thepressure tube was sealed. The reaction mixture was stirred overnight at100° C. After cooling to room temperature, the reaction mixture wasdiluted with a solution of 5% iPrOH/DCM (20 mL) and washed with water (5mL). The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to afford the title compound which was carriedforward without further purification. MS (apci) m/z=611.9, 612.8 (M+H).

Step 4: Preparation of6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A room temperature solution of tert-butyl4-(5-(3-cyano-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylatein TFA (2 mL) was stirred for 1 h at room temperature, and thenconcentrated in vacuo. The crude residue was purified by C18reverse-phase chromatography (5-80% ACN/water with 0.1% TFA as thegradient eluent) to cleanly afford the title compound as the TFA salt.The TFA salt was suspended in DCM (1 mL) containing a few drops of MeOH,then treated with 4 N HCl in dioxane (2 mL). The resulting mixture wasconcentrated and dried in vacuo to cleanly afford the title compound asthe dihydrochloride salt (45 mg, 43% yield). MS (apci) m/z=511.9 (M+H).

Step 5: Preparation of(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (31 mg, 0.053 mmol) in DMF (1.1 mL) was treated withD-alpha-Hydroxyisovaleric acid (7.5 mg, 0.064 mmol), HATU (24.2 mg,0.0636 mmol) and DIEA (46.2 μL, 0.265 mmol). The resulting solution wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with 5% MeOH/DCM (20 mL) and washed with water (5 mL). Thecombined organic extracts were dried over anhydrous MgSO₄, then filteredand concentrated in vacuo. The crude residue was purified by silicachromatography (8% MeOH/DCM with 2% NH₄OH_((aq)) as the eluent) tocleanly afford the title compound (20 mg, 62% yield). MS (apci)m/z=611.9, 612.9 (M+1).

Example 716

(R)-6-(1-(3-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-3-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Example 636; 8 mg, 0.0158 mmol), (S)-3-bromo-2-methylpropan-1-ol (2.91mg, 0.0190 mmol) and Cs₂CO₃ (25.8 mg, 0.0791 mmol) in DMA (200 μL) wasstirred overnight at ambient temperature, then purified directly by C18reverse-phase chromatography (0-60% ACN/water as the gradient eluent) toafford the title compound (3.3 mg, 36% yield). MS (apci) m/z=578.3(M+H).

Example 717

(S)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(2-methyloxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 624; 21.3 mg, 0.0465 mmol) in dry DMF (500 μL)was treated sequentially with DIEA (24.3 μL, 0.139 mmol), HATU (26.5 mg,0.0697 mmol) and (S)-2-hydroxy-2-phenylacetic acid (10.6 mg, 0.0697mmol). The resulting solution was stirred 4 d at ambient temperature,during which time additional amounts of DIEA, HATU and(R)-2-hydroxy-2-phenylacetic acid were added (1 equivalent/day of each,total of 3 additional equivalents of each reagent) in an effort to drivethe reaction to completion. The reaction mixture was quenched withwater/CHCl₃, and the resulting biphasic mixture was extracted with CHCl₃in a PS Frit. The combined organic extracts were concentrated in vacuoand purified by C18 reverse-phase chromatography (25-80% ACN in waterwith 0.1% formic acid as the gradient eluent) to afford the titlecompound (2.3 mg, 10% yield). MS (apci) m/z=520.2 (M+H).

Example 718

(R)-4-(6-(4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Following a similar method to that used in Step 2 for the preparationand purification of Example 717, replacing (S)-2-hydroxy-2-phenylaceticacid with (R)-2-hydroxy-2-phenylacetic acid, the title compound wasisolated cleanly (2.6 mg, 11% yield). MS (apci) m/z=520.2 (M+H).

Example 719

(S)-4-(6-(4-(2-methoxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Following a similar method to that used in Step 2 for the preparationand purification of Example 717, replacing (S)-2-hydroxy-2-phenylaceticacid with (S)-2-methoxy-2-phenylacetic acid, omitting the addition ofextra reagents and using anhydrous Na₂SO₄ rather than the PS Frit as thedrying agent, the title compound was isolated cleanly (6.3 mg, 32%yield). MS (apci) m/z=534.2 (M+H).

Example 720

(R)-4-(6-(4-(2-methoxy-2-phenylacetyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Following a similar method to that used in Step 2 for the preparationand purification of Example 717, replacing (S)-2-hydroxy-2-phenylaceticacid with (R)-2-methoxy-2-phenylacetic acid, and omitting the additionof extra reagents, the title compound was isolated cleanly (4.3 mg, 18%yield). MS (apci) m/z=534.2 (M+H).

Example 721

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(2-methyloxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 624; 20.1 mg, 0.0439 mmol) in dry DMA (500 μL)was treated with TEA (18.3 μL, 0.132 mmol), Me₄N(AcO)₃BH (17.3 mg,0.0658 mmol) and 6-methoxynicotinaldehyde (9.02 mg, 0.0658 mmol). Theresulting mixture was stirred at ambient temperature for 5 hours, beforeintroducing additional TEA (6.1 μL, 0.044 mmol), Me₄N(AcO)₃BH (11.5 mg,0.044 mmol) and 6-methoxynicotinaldehyde (6.01 mg, 0.044 mmol). Thereaction mixture was stirred overnight at ambient temperature, thentreated with additional TEA and 6-methoxynicotinaldehyde (20 μL ofeach). The reaction mixture was stirred for an additional 3 d beforequenching with water/CHCl₃. The quenched mixture was extracted withCHCl₃ in a PS Frit, and the combined organic extracts were concentratedin vacuo. The crude residue was purified by C18 reverse-phasechromatography (15-80% ACN/water as the gradient eluent) to afford thetitle compound (2.7 mg, 12% yield). MS (apci) m/z=506.8 (M+H).

Example 722

6-(2-methyloxazol-5-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(2-methyloxazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 624; 21.7 mg, 0.0473 mmol) in dry DMA (500 μL)was treated sequentially with TEA (19.8 μL, 0.142 mmol), Me₄N(AcO)₃BH(18.7 mg, 0.071 mmol) and picolinaldehyde (6.8 μL, 0.071 mmol). Theresulting mixture was stirred at ambient temperature for 5 hours beforeintroducing additional TEA (6.6 μL, 0.048 mmol), Me₄N(AcO)₃BH (12.5 mg,0.047 mmol) and picolinaldehyde (4.5 μL, 0.047 mmol). The reactionmixture was stirred overnight at ambient temperature, then quenched withwater/CHCl₃. The quenched mixture was extracted with CHCl₃ in a PS Frit,and the combined organic extracts were concentrated in vacuo. The cruderesidue was purified by C18 reverse-phase chromatography (15-90%ACN/water as the gradient eluent) to afford the title compound (4.4 mg,20% yield). MS (apci) m/z=477.2 (M+H).

Example 723

(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate Step 1: Preparation of tert-butyl4-(5-(3-cyano-6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube, a mixture of tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P14; 100 mg, 0.181 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (48.9mg, 0.217 mmol), Pd₂(dba)₃.CHCl₃ (9.37 mg, 0.00905 mmol), XPhos (17.3mg, 0.0362 mmol) and K₂CO_(3(s)) (75.0 mg, 0.543 mmol) in 4:1dioxane/water (1.81 mL) was sparged for 5 min with N_(2(g)). The vesselwas sealed and the reaction mixture was stirred overnight at 100° C.After cooling to room temperature, the reaction mixture was diluted withEtOAc (20 mL) and washed with water (5 mL). The organic extracts weredried over anhydrous MgSO₄, filtered, and concentrated in vacuo. Thecrude residue was purified by silica chromatography (2-40% acetone/DCMas the gradient eluent) to afford the title compound (80 mg, 88% yield).MS (apci) m/z=502.2 (M+H).

Step 2: Preparation of6-(2-methylthiazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A solution of tert-butyl 4-(5-(3-cyano-6-(2-methylthiazol5-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(78 g, 156 mmol) in TFA (2 mL) was stirred for 30 min at ambienttemperature, and then concentrated in vacuo. The residue was dissolve inDCM (1 mL) and treated with 4 N HCl (2 mL) in dioxane. The resultingsuspension was stirred for 10 min at ambient temperature. The mixturewas concentrated in vacuo, azeotroping with ACN to cleanly afford thetitle compound as the dihydrochloride salt which was carried on withoutfurther purification. MS (apci) m/z=402.1 (M+H).

Step 3: Preparation of(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A solution of6-(2-methylthiazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (42 mg, 0.0885 mmol) in DCM (3 mL) was treated with DIEA(61.7 μL, 0.354 mmol), D-alpha-Hydroxyisovaleric acid (12.5 mg, 0.106mmol) and HATU (40.4 mg, 0.106 mmol). The resulting solution was stirredovernight at ambient temperature. The reaction mixture was concentratedin vacuo, and the crude residue was purified by C18 reverse-phasechromatography (5-95% ACN/water with 0.1% TFA as the gradient eluent) tocleanly afford the title compound as the bistrifluoroacetate salt (15mg, 28% yield). MS (apci) m/z=502.2 (M+H).

Example 724

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate Step 1: Preparation of6-(2-methylthiazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(2-methylthiazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 723, Step 2; 37 mg, 0.0780 mmol) in MeOH (7.8mL) and water (2 mL) containing several drops of AcOH was extracted with5% iPrOH/DCM (30 mL). The organic extracts were washed with saturatedNaHCO_(3(aq)) and brine. The neutralized organic phase was then driedover anhydrous MgSO₄, filtered, and concentrated in vacuo to afford thetitle compound as the free base (28 mg, 90% recovery). MS (apci)m/z=502.2 (M+H).

Step 2: Preparation of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A solution of6-(2-methylthiazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(28.0 mg, 0.0697 mmol) in MeOH (2.0 mL) was treated sequentially with6-methoxynicotinaldehyde (19.1 mg, 0.139 mmol), NaBH(AcO)₃ (41 mg, 0.209mmol) and 2-3 drops of AcOH. The resulting mixture was stirred atambient temperature overnight. About 60% of unreacted starting materialremained in the mixture. Therefore, additional acetic acid (0.5 mL) wasadded and the reaction mixture was stirred for another 24 h, but thisfailed to drive the reaction to completion. Therefore the mixture wasconcentrated in vacuo. The residue obtained was re-suspended in DCM (10mL) and re-treated with 6-methoxynicotinaldehyde (30.7 mg, 0.224 mmol),NaBH(AcO)₃ (65.8 mg, 0.336 mmol) and AcOH (1 mL). The resulting mixturewas stirred for 36 h at ambient temperature and then quenched withwater. The quenched mixture was extracted with DCM. The combined organicextracts were dried over anhydrous MgSO₄, filtered, and concentrated invacuo. The crude residue was purified by C18 reverse-phasechromatography (5-95% ACN/water with 0.1% TFA as the gradient eluent) toafford the title compound as the mono trifluoroacetate salt (12.7 mg,12% yield). MS (apci) m/z=523.2 (M+H).

Example 725

6-(2,4-dimethylthiazol-5-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-(5-(3-cyano-6-(2,4-dimethylthiazol-5-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube, a mixture of tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P14; 50 mg, 0.0905 mmol),2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole(26.0 mg, 0.109 mmol), Pd₂(dba)₃.CHCl₃ (4.68 mg, 0.00452 mmol), XPhos(8.63 mg, 0.0181 mmol) and K₂CO_(3(s)) (37.5 mg, 0.271 mmol) in 4:1dioxane/water (0.91 mL) was sparged for 5 min with N_(2(g)). Thepressure tube was sealed and the reaction mixture was stirred overnightat 100° C. After cooling to room temperature, the reaction mixture wasdiluted with EtOAc (20 mL) and washed with water (5 mL). The organiclayer was dried over anhydrous MgSO₄, filtered, and concentrated invacuo. The crude residue was purified by silica chromatography (30%acetone/DCM as the eluent) to afford the title compound (58.2 mg,quantitative yield). MS (apci) m/z=516.2 (M+H).

Step 2: Preparation of6-(2,4-dimethylthiazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A solution of tert-butyl4-(5-(3-cyano-6-(2,4-dimethylthiazol-5-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(45 mg, 0.087 mmol) in TFA (2 mL) was stirred for 20 min at ambienttemperature, and then concentrated in vacuo. The residue was dissolvedin DCM (2 mL) and treated with a solution of 4 N HCl in dioxane (2 mL).After stirring for 10 min at ambient temperature, the suspension wasconcentrated in vacuo to afford the title compound as thedihydrochloride salt which was used in the next step without furtherpurification (41 mg, 96% yield). MS (apci) m/z=416.2 (M+H).

Step 3: Preparation of4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A mixture of6-(2,4-dimethylthiazol-5-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(45 mg, 0.108 mmol) in methanol (1083 μL, 0.108 mmol) was sequentiallytreated with 6-methoxynicotinaldehyde (29.7 mg, 0.217 mmol), Na(OAc)₃BH(63.7 mg, 0.325 mmol) and 2-3 drops of acetic acid. The resultingmixture was stirred at ambient temperature overnight to reach about 50%conversion by LCMS. The mixture was re-treated with additional6-methoxynicotinaldehyde (29.7 mg, 0.217 mmol), Na(OAc)₃BH (63.7 mg,0.325 mmol) and a few drops of acetic acid and allowed to stir atambient temperature over 48 h. The reaction still did not go tocompletion (LCMS). Additional acetic acid (0.5 mL) was added and themixture was allowed to stir at ambient temperature for another 24 h.This failed to drive the reaction to completion. The mixture wasretreated with additional acetic acid (0.5 mL) and stirred at 45° C. for4 hours before it was concentrated in vacuo. The resulting residue wastaken up in DCE (5 mL), then re-treated with 6-methoxynicotinaldehyde(29.7 mg, 0.217 mmol), Na(OAc)₃BH (63.7 mg, 0.325 mmol) and few drops ofacetic acid. The resulting mixture was stirred at ambient temperature.After 24 h the mixture was diluted with DCM (15 mL) and washed withbrine (5 mL). The organic layer was separated, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by silica chromatography(5-75% acetone/hexanes) to provide the title product as a solid (10.1mg, 17.4% yield). MS (apci) m/z=537.2 (M+H).

Example 726

6-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate Step 1: Preparation of tert-butyl4-(5-(3-cyano-6-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube, a mixture of tert-butyl4-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Intermediate P14; 200 mg, 0.362 mmol), Cu(I)I (13.8 mg, 0.0724 mmol),PdCl₂(PPh₃)₂ (25.4 mg, 0.0362 mmol), TEA (151 μL, 1.09 mmol), and PPh₃(4.75 mg, 0.0181 mmol) in DMF (1.45 mL) was sparged for 5 min withN_(2(g)). The sparged mixture was treated with ethynyltrimethylsilane(60.2 μL, 0.434 mmol), and sparged again for 5 min with N_(2(g)), beforesealing the vessel. The reaction mixture was stirred for 6 h at 65° C.,then overnight at ambient temperature. The reaction mixture was pouredinto water (10 mL), and extracted with EtOAc. The combined organicextracts were washed with brine, then dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The crude product residue waspurified by silica chromatography (2-40% EtOAc/hexanes as the gradienteluent) to afford the title compound (142 mg, 78% yield). MS (apci)m/z=501.2 (M+H).

Step 2: Preparation of tert-butyl4-(5-(3-cyano-6-ethynylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-(5-(3-cyano-6-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(140 mg, 0.280 mmol) in MeOH (2.8 mL) was treated with powdered K₂CO₃(11.6 mg, 0.0839 mmol). The resulting mixture was stirred for 3 h atambient temperature, before concentrating the mixture in vacuo. Theresulting residue was partitioned between EtOAc (50 mL) and water (10mL). The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude product residue was purified by silicachromatography (10-70% acetone/DCM as the gradient eluent) to afford thetitle compound (121.3 mg, quantitative yield). MS (apci) m/z=492.2(M+H).

Step 3: Preparation of tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

A slurry of tert-butyl4-(5-(3-cyano-6-ethynylpyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(55 mg, 0.13 mmol) in 1:1 t-BuOH:H₂O (2 mL) was treated with CuSO₄ (4.1mg, 0.026 mmol), sodium(R)-5-((S)-1,2-dihydroxyethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-olate(13 mg, 0.064 mmol) and (azidomethyl)trimethylsilane (17 mg, 0.13 mmol).The resulting reaction mixture was stirred for 15 h at ambienttemperature before introducing additional (azidomethyl)trimethylsilane(10 mg, 0.076 mmol), and sodium(R)-5-((S)-1,2-dihydroxyethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-olate(13 mg, 0.064 mmol), CuSO₄ (4.1 mg, 0.026 mmol). The mixture then wasstirred for an additional 3d at ambient temperature before diluting themixture with water (20 mL). The aqueous mixture was extracted with EtOAc(3×30 mL). The combined organic extracts were dried over anhydrousMgSO₄, filtered, and concentrated in vacuo to afford the intermediatetert-butyl4-(5-(3-cyano-6-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(MS apci (m/z)=558.3 (M+H)) and unreacted alkyne. The crude mixture wasdissolved in THF (2 mL), and treated with 1 M TBAF in THF (128 L, 0.13mmol). The resulting reaction mixture was stirred for 2 h at ambienttemperature, then diluted with EtOAc (30 mL) and washed with water (10mL). The organic extracts were washed with brine (10 mL), dried overanhydrous MgSO₄, filtered, and concentrated in vacuo to afford a 2:1mixture of the title compound (about 41 mg, 66% yield, based on LCMS %and total mass; MS (apci) m/z=486.2 (M+H)) and some unreacted alkyne.The crude mixture was used in the next step without purification.

Step 4: Preparation of6-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A solution of the impure tert-butyl4-(5-(3-cyano-6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(41 mg, 0.084 mmol) in TFA (2 mL) was stirred for 1 h at ambienttemperature, and then concentrated in vacuo to afford the title compoundin a 2:1 ratio with the unreacted alkyne carried over from Step 3. TheTFA salt of the pure title compound (27 mg, 42% overall yield from Step2) was isolated by purification of the impure mixture by C18reverse-phase chromatography (5-95% ACN/water with 0.1% TFA as thegradient eluent). MS (apci) m/z=385.9, 386.9 (M+H).

Example 727

(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate Step 1: Preparation of6-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

A solution of6-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate (Example 726, Step 4; 27 mg, 0.0541 mmol) in 4 NHCl in dioxane (2 mL) was stirred for 5 min at ambient temperature. Themixture was concentrated in vacuo, azeotroping with MeOH, to afford thetitle compound (22 mg, 96% yield). This material was used directly inStep 2 without further purification or analysis.

Step 2: Preparation of(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A suspension of6-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride (22 mg, 0.0521 mmol) in DMF (1.5 mL) was treated with DIEA(45.4 μL, 0.261 mmol), D-alpha-Hydroxyisovaleric acid (7.39 mg, 0.0626mmol) and HATU (23.8 mg, 0.0626 mmol). The resulting solution wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with 5% MeOH/DCM (20 mL) and washed with water (5 mL). Theorganic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude residue was triturated with 2:1MeOH:TFA (2.25 mL). The precipitate that formed was collected byfiltration, then rinsed with ACN (0.5 mL) and dried in vacuo to cleanlyafford the title compound as the trifluoroacetate salt (12 mg, 38%yield). MS (apci) m/z=485.8, 486.9 (M+H).

Example 728

tert-butyl4-(5-(3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylateStep 1: Preparation of4-methoxy-6-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube, a mixture of6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (IntermediateP4; 1.0 g, 3.97 mmol), Cu(I)I (0.151 g, 0.793 mmol), PdCl₂(PPh₃)₂ (0.278g, 0.397 mmol), TEA (1.66 mL, 11.9 mmol), and PPh₃ (52 mg, 0.198 mmol)in DMF (16 mL) was sparged for 5 min with N_(2(g)). The sparged mixturewas treated with ethynyltrimethylsilane (659 μL, 4.76 mmol) and flushedwith N_(2(g)), before sealing the vessel. The reaction mixture wasstirred for 6 h at 65° C., then overnight at ambient temperature. Atroom temperature, the reaction mixture was poured into water (20 mL),and extracted with EtOAc (2×50 mL). The combined organic extracts werewashed with brine (10 mL), then dried over anhydrous MgSO₄, filtered,and concentrated in vacuo. The crude product residue was purified bysilica chromatography (2-40% EtOAc/hexanes as the gradient eluent) toafford the title compound (700 mg, 66% yield). ¹H NMR (400 MHz, CDCl₃)□□ 8.30 (d, J=0.78 Hz, 1H), 8.16 (s, 1H), 6.64 (d, J=0.78 Hz, 1H), 4.02(s, 3H), 0.26 (s, 9H)

Step 2: Preparation of6-ethynyl-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-methoxy-6-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitrile(Step 1; 0.7 g, 2.60 mmol) in MeOH (26 mL) was treated with powderedK₂CO₃ (0.108 g, 0.780 mmol). The resulting mixture was stirred for 3 hat ambient temperature before concentrating the mixture in vacuo. Theresulting residue was partitioned between EtOAc (100 mL) and water (30mL). The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to afford the title compound (530 mg, quantitativeyield), which was carried on without further purification. ¹HNMR (400MHz, CDCl₃) □□ 8.331 (d, J=1.17 Hz, 1H), 8.17 (s, 1H), 6.66 (d, J=0.78Hz, 1H), 4.04 (s, 3H), 3.16 (s, 1H).

Step 3: Preparation of6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of isopropyl bromide (1.43 mL, 15.2 mmol) and sodium azide(989 mg, 15.2 mmol) in 1:2 t-BuOH:H₂O (3 mL) was stirred for 2 h at 80°C. After cooling to ambient temperature, the reaction mixture wastreated with 6-ethynyl-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(300 mg, 1.52 mmol) and Cu(I)I (29.0 mg, 0.152 mmol). The resultingreaction mixture was stirred for 16 h at 80° C. The mixture was cooledto ambient temperature, diluted with EtOAc (100 mL) and washed withwater (30 mL). The organic extracts were dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The crude residue was trituratedwith ACN. The precipitate that formed was collected by filtration, thenrinsed with ACN and dried in vacuo to cleanly afford the title compound(294 mg, 69% yield). MS (apci) m/z=283.0 (M+H).

Step 4: Preparation of4-hydroxy-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Two batches of6-(1-Isopropyl-1H-1,2,3-triazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(total 290 mg) were processed as described below to provide the titlecompound.

Batch 1:6-(1-Isopropyl-1H-1,2,3-triazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(150 mg, 0.531 mmol) was suspended in 1,2-dichloroethane (5.3 mL, 0.531mmol) and heated to 80° C. At 50° C. the mixture became a clearsolution. The resulting solution was cooled to 50° C. and treated withAlCl₃ (283 mg, 2.13 mmol) and heated at reflux for 4 h with vigorousstirring. The mixture was then allowed to stir at ambient temperatureovernight and 80° C. for 3 h. The mixture was cooled to 0° C. and pouredinto a mixture of Na₂SO₄-10H₂O (3355 mg, 10.4 mmol) in THF (20 mL).

Batch 2: A second batch of6-(1-Isopropyl-1H-1,2,3-triazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(140 mg) was also processed as described above to obtain a second crudebatch of the title compound. The crude products obtained from the tworeactions were combined and purified by silica chromatography (1-10%MeOH/DCM) to provide the title compound (200 mg, 71.6% yield, from 290mg of starting material). MS (APCI+) m/z 269.1 (M+1).

Step 5: Preparation of3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

An ambient temperature solution of4-hydroxy-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(200 mg, 0.746 mmol) and DIEA (649 μL, 3.73 mmol) in THF (7.46 μL) wastreated with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(533 mg, 1.49 mmol). The resulting mixture was stirred for 6 h atambient temperature, and then stored in the freezer 3 d. The mixture waspoured into water (20 mL), and extracted with DCM (100 mL). The organicextracts were dried over anhydrous MgSO₄, filtered, and concentrated invacuo. The residue obtained was purified by silica chromatography(10-90% EtOAc/hexane as the gradient eluent) to afford the titlecompound (220 mg, 74% yield). ¹H NMR (400 MHz, CDCl₃) 09.08 (d, J=0.74Hz, 1H), 8.31 (s, 1H), 7.91 (d, J=0.78, 1H), 7.86 (s, 1H), 4.95-4.88 (m,1H), 1.65 (d, 6H).

Step 6: Preparation tert-butyl4-(5-(3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube, a mixture of3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (50 mg, 0.12 mmol), tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(49 mg, 0.12 mmol), Pd₂(dba)₃.CHCl₃ (6.5 mg, 0.0062 mmol), XPhos (12 mg,0.025 mmol), K₂CO_(3(s)) (52 mg, 0.37 mmol) in 4:1 dioxane/water (1.25mL) was sparged for 5 min with N_(2(g)), and subsequently the vessel wassealed. The reaction mixture was stirred overnight at 100° C. Aftercooling to room temperature, the reaction mixture was diluted with DCM(20 mL) and washed with water (5 mL). The organic extracts were driedover anhydrous MgSO₄, filtered, and concentrated in vacuo. The residueobtained was purified by silica chromatography (1-40% acetone/DCM as thegradient eluent) to afford the title compound (60 mg, 94% yield).MS(apci) m/z=513.8 (M+H).

Example 729

(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate Step 1: Preparation of6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

A solution of tert-butyl4-(5-(3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(Example 728, Step 6; 59 mg, 0.11 mmol) in TFA (2 mL) was stirred for 1h at ambient temperature. The resulting mixture was concentrated invacuo. The residue was dissolved in DCM (1 mL) and treated with 4 N HClin dioxane (2 mL). The resulting suspension was stirred for 10 min atambient temperature and then concentrated in vacuo to afford the titlecompound (55 mg, quantitative yield). MS (apci) m/z=413.9 (M+H).

Step 2: Preparation of(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate

A suspension of6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride (50 mg, 0.111 mmol) in DMF (1.5 mL) was treated with DIEA(96.8 μL, 0.556 mmol), D-alpha-Hydroxyisovaleric acid (15.8 mg, 0.133mmol) and HATU (50.7 mg, 0.133 mmol). The resulting solution was stirredovernight at ambient temperature. The reaction mixture was diluted with5% MeOH/DCM (20 mL), and washed with water (5 mL). The organic extractswere dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.The crude residue was purified by C18 reverse-phase chromatography(5-95% ACN/water with 0.1% TFA as the gradient eluent) to cleanly affordthe title compound as the trifluoroacetate salt (12 mg, 17% yield). MS(apci) m/z=513.9 (M+H).

Example 730

6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

In a pressure tube, a mixture of3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Example 728, Step 5; 50 mg, 0.12 mmol),1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(Example 697, Step 3; 61 mg, 0.15 mmol), Pd₂(dba)₃.CHCl₃ (6.5 mg, 0.0062mmol), XPhos (12 mg, 0.025 mmol), K₂CO_(3(s)) (52 mg, 0.37 mmol) in 4:1dioxane/water (1.25 mL) was sparged for 5 min with N_(2(g)), andsubsequently the vessel was sealed. The reaction mixture was stirredovernight at 100° C. After cooling to room temperature, the reactionmixture was diluted with 5% MeOH/DCM (20 mL), and washed with water (5mL). The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The residue obtained was purified by silicachromatography (5-70% acetone/DCM as the gradient eluent), and thenagain by C18 reverse-phase chromatography (5-95% ACN/water with 0.1% TFAas the gradient eluent) to afford the title compound as thebistrifluoroacetate salt (55 mg, 58% yield). MS(apci) m/z=534.8, 535.8(M+H).

Example 731

6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) Step 1: Preparation of1-(pyridin-2-ylmethyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine

A solution of1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(3 g, 10.4 mmol), in DCM (85 mL) was treated with picolinaldehyde (1.22g, 11.4 mmol). The resulting mixture was stirred for 1 h at ambienttemperature before introducing NaBH(OAc)₃ (4.40 g, 20.7 mmol). Theresulting mixture was stirred overnight at ambient temperature, and thenconcentrated in vacuo. The residue was dissolved in EtOAc, and washedsequentially with saturated NaHCO_(3(aq)) and brine. The organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The resulting thick oil was dissolved in minimal boiling EtOAc,and the resulting solution was allowed to cool. The crystals that formedwere collected by vacuum filtration, washed with hexanes and dried underhigh vacuum to cleanly afford the title compound (2.88 g, 73% yield). ¹HNMR (CDCl₃) δ 8.58-8.59 (m, 1H), 8.53 (m, 1H), 7.79-7.82 (m, 1H),7.65-7.69 (m, 1H), 7.43-7.45 (m, 1H), 7.16-7.20 (m, 1H), 6.56-6.59 (m,1H), 3.71 (s, 2H), 3.65 (t, 4H), 2.61 (t, 4H), 1.31 (s, 12H).

Step 2: Preparation of6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

In a pressure tube, a mixture of3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Example 728, Step 5; 50 mg, 0.12 mmol),1-(pyridin-2-ylmethyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(Step 1; 57 mg, 0.15 mmol), Pd₂(dba)₃.CHCl₃ (6.5 mg, 0.0062 mmol), XPhos(12 mg, 0.025 mmol), K₂CO_(3(s)) (52 mg, 0.37 mmol) in 4:1 dioxane/water(1.25 mL) was sparged for 5 min with N_(2(g)), and subsequently thevessel was sealed. The reaction mixture was stirred overnight at 90° C.After cooling to room temperature, the reaction mixture was diluted with5% MeOH/DCM (20 mL), and washed with water (5 mL). The organic layer wasdried over anhydrous MgSO₄, filtered, and concentrated in vacuo. Theresidue obtained was purified by C18 reverse-phase chromatography (5-80%ACN/water with 0.1% TFA as the gradient eluent) to afford the titlecompound as the bistrifluoroacetate salt (3 mg, 3% yield). MS(apci)m/z=504.8 (M+H).

Example 732

6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-(6-(4-(pyrimidin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate) Step 1: Preparation of2-((4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrimidine

A solution of1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(1.0 g, 3.5 mmol), 2-(chloromethyl)pyrimidine hydrochloride (0.68 g, 4.1mmol), and Cs₂CO₃ (2.8 g, 8.6 mmol) in DMF (6 mL) was stirred overnightat ambient temperature, and then at 50° C. until LCMS indicated reactioncompletion. After cooling to ambient temperature, the reaction mixturewas diluted with MTBE (20 mL), and extracted sequentially with 1:1water: saturated NaHCO_(3(aq)) (5 mL) and brine (3×5 mL). The organicextracts were dried over anhydrous MgSO₄, filtered, and concentrated invacuo. The residue obtained was purified by silica chromatography (1-25%DCM-MeOH as the gradient eluent) to afford the title compound (500 mg,38% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.76-8.75 (d, 2H), 8.54-8.53 (d,1H), 7.82-7.79 (dd, 1H), 7.22-7.20 (t, 1H), 6.59-6.57 (d, 1H), 3.88 (s,2H), 3.71-3.68 (m, 4H), 2.70-2.68 (m, 4H), 1.31 (s, 12H).

Step 2: Preparation of6-(1-isopropyl-1H-1,2,3-triazol-4-yl)-4-(6-(4-(pyrimidin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate)

In a pressure tube, a mixture of3-cyano-6-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Example 728, Step 5; 50 mg, 0.12 mmol),2-((4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrimidine(Step 1; 57 mg, 0.15 mmol), Pd₂(dba)₃.CHCl₃ (6.5 mg, 0.0062 mmol), XPhos(12 mg, 0.025 mmol), and K₂CO_(3(s)) (52 mg, 0.37 mmol) in 4:1dioxane/water (1.25 mL) was sparged for 5 min with N_(2(g)), and thevessel was sealed. The reaction mixture was stirred overnight at 100° C.After cooling to room temperature, the reaction mixture was diluted with5% MeOH/DCM (20 mL), and washed with water (5 mL). The organic extractswere dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.The residue obtained was purified by C18 reverse-phase chromatography(5-80% ACN/water with 0.1% TFA as the gradient eluent) to afford thetitle compound as the bistrifluoroacetate salt (42 mg, 46% yield).MS(apci) m/z=505.8, 506.8 (M+H).

Example 733

6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of6-bromo-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile(Intermediate P17; 2.0 g, 8.40 mmol) in DMA (33.6 mL) was treated withK₂CO_(3(s)) (3.48 g, 25.2 mmol), and stirred for 10 min at ambienttemperature before reducing the temperature to 0° C. The 0° C. mixturethen was treated dropwise with chloro(methoxy)methane (0.766 mL, 10.1mmol). After stirring the resultant mixture for 10 min at 0° C., themixture was stirred overnight at ambient temperature. The reactionmixture was poured into ice water (300 mL) and stirred for 1 h atambient temperature. The resulting suspension was filtered, and theisolated solids were rinse with water and reserved. The filtrate wasextracted with DCM (4×50 mL). The combined organic extracts were driedover anhydrous MgSO₄, filtered, and concentrated in vacuo. The crudeproduct residue was triturated with ACN/Hexanes. The solid from thetrituration was combined with the reserved solids to afford the titlecompound (2.34 mg, 99% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J=1.17Hz, 1H), 8.137 (s, 1H), 7.09 (d, J=1.17 Hz, 1H), 5.38 (s, 2H), 3.56 (s,3H).

Step 2: Preparation of4-(methoxymethoxy)-6-((trimethylsilyl)ethinyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-bromo-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.22g, 4.32 mmol), Cu(I)I (0.165 g, 0.865 mmol), PdCl₂(PPh₃)₂ (0.304 g,0.432 mmol), TEA (1.81 mL, 13.0 mmol), and PPh₃ (56.7 mg, 0.216 mmol) inDMF (17 mL) was sparged for 5 min with N_(2(g)). The sparged mixture wastreated with ethynyltrimethylsilane (659 μL, 4.76 mmol), and spargedagain for 5 min with N_(2(g)). The reaction mixture was stirred under aN_(2(g)) atmosphere for 5 h at ambient temperature. The resultingmixture was poured into water (50 mL) and extracted with EtOAc (3×70mL). The combined organic extracts were washed with brine (20 mL), thendried over anhydrous MgSO₄, filtered, and concentrated in vacuo. Thecrude product residue was purified by silica chromatography (1-25%EtOAc/hexanes as the gradient eluent) to afford the title compound (1.1g, 85% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J=1.17 Hz, 1H), 8.17(s, 1H), 6.96 (d, J=1.17 Hz, 1H), 5.38 (s, 2H), 3.56 (s, 3H), 0.253 (s,9H).

Step 3: Preparation of6-ethynyl-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of4-(methoxymethoxy)-6-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitrile(1.1 g, 3.67 mmol) in MeOH (37 mL) was treated with powdered K₂CO₃(0.152 g, 1.10 mmol). The resulting mixture was stirred overnight atambient temperature, before concentrating the mixture in vacuo. Theresulting residue was partitioned between EtOAc (150 mL) and water (30mL). The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude product residue was purified by silicachromatography (1-40% EtOAc/Hexanes as the gradient eluent) to affordthe title compound (760 mg, 91% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.37(d, J=0.78 Hz, 1H), 8.19 (s, 1H), 7.00 (d, J=1.17 Hz, 1H), 5.38 (s, 2H),3.56 (s, 3H), 3.16 (s, 1H).

Step 4: Preparation of6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 1-bromo-2-methoxyethane (901.6 μL, 9.59 mmol) and sodiumazide (623.7 mg, 9.59 mmol) in 1:2 t-BuOH:H₂O (1.92 mL) was stirred for2 h at 80° C. After cooling to ambient temperature, the reaction mixturewas treated with6-ethynyl-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (218mg, 0.96 mmol) and Cu(I)I (18.27 mg, 0.096 mmol). The resulting reactionmixture was stirred for 1 h at 80° C. The mixture was cooled to ambienttemperature and diluted with water (50 mL). The resulting suspension wasstirred for 30 min at ambient temperature. The precipitate that formedwas collected by filtration, then rinsed with water (2×10 mL), and driedin vacuo to cleanly afford the title compound (316 mg, 100% yield). MS(apci) m/z=328.9, 329.9 (M+H).

Step 5: Preparation of4-hydroxy-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride

A suspension of6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile(315 mg, 0.959 mmol) in THF (4 mL) was treated with 4 N HCl_((aq)) andstirred overnight at ambient temperature. The mixture was concentratedin vacuo and the residue was dried under high vacuum to afford the titlecompound as the hydrochloride salt (257 mg, 84% yield). MS (apci)m/z=284.9 (M+H).

Step 6: Preparation of3-cyano-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate

An ambient temperature solution of4-hydroxy-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilehydrochloride (Step 5; 255 mg, 0.795 mmol) in THF (7.46 μL) was treatedsequentially with DIEA (831 μL, 4.77 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)-methanesulfonamide(568 mg, 1.59 mmol). The resulting mixture was stirred for 2 h atambient temperature. The mixture was poured into water (20 mL), andextracted with EtOAc (100 mL). The organic extracts were dried overanhydrous MgSO₄, filtered, and concentrated in vacuo. The residueobtained was purified by silica chromatography (1-55% acetone/DCM as thegradient eluent) to afford the title compound (380 mg, quantitativeyield). ¹H NMR (400 MHz, CDCl₃) δ 9.07 (d, J=1.17 Hz, 1H), 8.31 (s, 1H),7.94 (d, J=1.17 Hz, 1H), 4.62 (m, 2H), 3.79 (m, 2H), 3.39 (s, 3H).

Step 7: Preparation6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

In a pressure tube, a mixture of3-cyano-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (50 mg, 0.12 mmol),1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(Example 697, Step 3; 59 mg, 0.14 mmol), Pd₂(dba)₃ (6.2 mg, 0.0060mmol), XPhos (11 mg, 0.024 mmol), K₂CO_(3(s)) (50 mg, 0.36 mmol) in 4:1dioxane/water (1.20 mL) was sparged for 5 min with N_(2(g)), andsubsequently the vessel was sealed. The reaction mixture was stirredovernight at 100° C. After cooling to room temperature, the reactionmixture was diluted with 5% MeOH/DCM (20 mL), and washed with water (5mL). The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica chromatography(5-70% acetone/DCM as the gradient eluent), and the isolated solids weretriturated with MeOH to cleanly afford the title compound (4.5 mg, 7%yield). MS(apci) m/z=551.2 (M+H).

Example 734

(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of tert-butyl4-(5-(3-cyano-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

In a pressure tube, a mixture of3-cyano-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Example 733, Step 6; 150 mg, 0.360 mmol),tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(154 mg, 0.396 mmol), Pd₂(dba)₃.CHCl₃ (18.6 mg, 0.0180 mmol), XPhos(34.4 mg, 0.0721 mmol), and K₂CO_(3(s)) (149 mg, 1.08 mmol) werecombined in 4:1 dioxane/water (3.60 mL). The mixture was sparged for 5min with N_(2(g)), and the vessel was sealed. The reaction mixture wasstirred overnight at 100° C. After cooling to room temperature, thereaction mixture was diluted with DCM (20 mL), and washed with water (5mL). The organic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The residue obtained was purified by silicachromatography (1-40% acetone/DCM as the gradient eluent), andsubsequently the isolated solids were triturated with MeOH to cleanlyafford the title compound (130 mg, 68% yield). MS(apci) m/z=530.2 (M+H).

Step 2: Preparation of6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride

A solution of tert-butyl4-(5-(3-cyano-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate(128 mg, 0.242 mmol) in TFA (3 mL) was stirred for 1 h at ambienttemperature. The resulting mixture was concentrated in vacuo. Theresidue obtained was dissolved in DCM (1 mL) and treated with 4 N HCl indioxane (3 mL). The resulting suspension was stirred for 5 min atambient temperature before concentrating the mixture in vacuo to affordthe title compound (130 mg, quantitative yield). MS (apci) m/z=430.2(M+H).

Step 3: Preparation of(R)-4-(6-(4-(2-hydroxy-3-methylbutanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (40 mg, 0.0796 mmol) in DMF (1.6 mL) was treated withD-alpha-Hydroxyisovaleric acid (11.3 mg, 0.0955 mmol), HATU (36.3 mg,0.0955 mmol) and DIEA (69.3 μl, 0.398 mmol). The resulting solution wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with 5% MeOH/DCM (20 mL) and washed with water (5 mL). Theorganic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silicachromatography (1-55% acetone/DCM as the gradient eluent) to cleanlyafford the title compound (2 mg, 5% yield). MS (apci) m/z=530.2 (M+H).

Example 735

4-(5-(3-cyano-6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperazine-1-carboxamide

A solution of6-(1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 734, Step 2; 40 mg, 0.0796 mmol) in DCM (2.65mL) was treated with TEA (66.6 μL, 0.478 mmol), and stirred for 15 minat ambient temperature. The reaction mixture was treated with1-isocyanato-2-methylpropane (9.87 μL, 0.0876 mmol). The resultingmixture was stirred for 3 h at ambient temperature, before quenchingwith water (1 mL). The quenched reaction mixture was extracted with DCM(3×10 mL), and the combined organic extracts were dried over anhydrousMgSO₄, filtered, and concentrated in vacuo. The residue was trituratedwith MeOH (2 mL). The resulting solids were filtered, washed withadditional MeOH (1 mL) and dried in vacuo to cleanly afford the titlecompound (2 mg, 5% yield). MS (apci) m/z=529.2 (M+H).

Example 736

4-(5-fluoro-6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrileStep 1: Preparation of4-(5,6-difluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P5; 150 mg, 0.404 mmol),(5,6-difluoropyridin-3-yl)boronic acid (89.9 mg, 0.566 mmol), Pd₂(dba)₃(18.5 mg, 0.0202 mmol), XPhos (38.5 mg, 0.0808 mmol), and 2 MNa₂CO_(3(aq)) (0.505 mL, 1.01 mmol) in dioxane (2.0 mL) was sparged for5 min with argon. The vessel was sealed and the reaction mixture wasstirred overnight at 90° C. After cooling to room temperature, thereaction mixture was purified directly by silica chromatography (1-10%DCM:MeOH as the gradient eluent) to cleanly afford the title compound(36 mg, 27% yield).

Step 2: Preparation of4-(5-fluoro-6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of4-(5,6-difluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile(0.036 g, 0.107 mmol), 1-((6-methoxypyridin-3-yl)methyl)piperazine (26.6mg, 0.128 mmol) and K₂CO₃ (29.6 mg, 0.214 mmol) in DMSO (1.07 mL) wasstirred overnight at 80° C. After cooling to ambient temperature, thereaction mixture was partitioned between DCM and water. The organicextracts were washed sequentially with water and brine, then dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude productresidue was purified by C18 reverse-phase chromatography (5-95%ACN/water with 0.1% TFA as the gradient eluent) to afford the titlecompound as the TFA salt. The TFA salt was dissolved in DCM andextracted with saturated Na₂CO_(3(aq)). The organic extracts were washedwith brine, then dried over anhydrous Na₂SO₄, filtered, and concentratedin vacuo to afford the title compound (29.2 mg, 52% yield). MS (apci)m/z=524.2 (M+H).

Example 737

6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 281; 10 mg, 0.022 mmol) in DMA (0.1 mL) wastreated sequentially with picolinaldehyde (3.0 mg, 0.028 mmol),Me₄N(AcO)₃BH (8.6 mg, 0.033 mmol) and TEA (9.1 μL, 0.065 mmol). Thereaction mixture was stirred for 20 h at ambient temperature, and thendirectly purified by C18 reverse-phase chromatography (0-70% ACN/wateras the gradient eluent) followed by C18 reverse-phase chromatography(0-70% ACN/water with 0.1% formic acid as the gradient eluent) tocleanly afford the title compound (1.2 mg, 12% yield). MS (apci)m/z=477.2 (M+H).

Example 738

6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-(pyridin-2-ylmethyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 291; 25 mg, 0.055 mmol) in DMA (0.1 mL) wastreated sequentially with picolinaldehyde (7.6 mg, 0.071 mmol),Me₄N(AcO)₃BH (22 mg, 0.082 mmol) and TEA (23 μL, 0.16 mmol). Thereaction mixture was stirred for 20 h at ambient temperature, and thendirectly purified by C18 reverse-phase chromatography (0-70% ACN/wateras the gradient eluent) to afford the title compound (23 mg, 88% yield).MS (apci) m/z=475.2 (M+H).

Example 739

6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-(pyrimidin-2-ylmethyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 291; 10 mg, 0.022 mmol) in DMA (0.1 mL) wastreated sequentially with pyrimidine-2-carbaldehyde (3.1 mg, 0.028mmol), Me₄N(AcO)₃BH (8.6 mg, 0.033 mmol) and TEA (9.2 μL, 0.066 mmol).The reaction mixture was stirred for 20 h at ambient temperature, andthen directly purified by C18 reverse-phase chromatography (0-70%ACN/water as the gradient eluent) to afford the title compound (6.5 mg,62% yield). MS (apci) m/z=476.2 (M+H).

Example 740

4-(4-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitriledihydrochloride (Example 291; 25 mg, 0.055 mmol) in DMA (0.1 mL) wastreated sequentially with 6-methoxynicotinaldehyde (3.9 mg, 0.028 mmol),Me₄N(AcO)₃BH (8.6 mg, 0.033 mmol) and TEA (9.2 μL, 0.066 mmol). Thereaction mixture was stirred for 20 h at ambient temperature, and thendirectly purified by C18 reverse-phase chromatography (0-65% ACN/wateras the gradient eluent) to afford the title compound (2.3 mg, 21%yield). MS (apci) m/z=505.2 (M+H).

Example 741

3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrimidin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

A mixture of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine(Example 644; 49.9 mg, 0.127 mmol) in 1:1 DCM:MeOH (1.2 mL) was treatedwith DIEA (29 μL, 0.16 mmol). After stirring for 5 min, the mixture wastreated sequentially with 2-pyrimidinecarboxaldehyde (27.4 mg, 0.253mmol), NaBH(AcO)₃ (53.7 mg, 0.253 mmol) and a couple of drops of AcOH.The resulting mixture was stirred at ambient temperature for 5 d,introducing additional reagents, 2-pyrimidinecarboxaldehyde (27 mg),NaBH(AcO)₃ (54 mg) and AcOH (2 drops), 3 times at 24 h intervals duringthe first 3 days of the time course. Upon completion, as determined byLCMS, the reaction mixture was diluted with DCM, and washed withsaturated NaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byC18 reverse-phase chromatography (5-95% ACN/water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The saltwas dissolved in 4:1 DCM:iPrOH, and extracted with saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(41.9 mg, 68% yield). MS (apci) m/z=486.2, 487.2 (M+H).

Example 742

3-chloro-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

In a pressure vessel, a solution of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (52.7 mg, 0.138 mmol) (Intermediate P8; 52.7mg, 0.138 mmol) in 4:1 dioxane:water (1.4 mL) was treated with1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(Example 697, Step 3; 62.5 mg, 0.152 mmol), Pd₂(dba)₃ (6.3 mg, 0.0069mmol), XPhos (13.2 mg, 0.028 mmol), and K₂CO_(3(aq)) (57.4 mg, 0.415mmol). After sparging the mixture with Ar_((g)), the vessel was sealed.The reaction mixture was stirred for 16 h at 90° C. After cooling toambient temperature, the mixture was diluted 4:1 DCM:iPrOH, and washedwith water. The organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by C18reverse-phase chromatography (5-95% ACN/water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The saltwas diluted with 4:1 DCM:iPrOH, and treated with saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(49 mg, 69% yield). MS (apci) m/z=515.2, 516.2 (M+H).

Example 743

3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyrimidin-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine

A solution of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P27; 52.0 mg, 0.144 mmol) in 4:1dioxane:water (1.4 mL) was treated with2-((4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrimidine(Example 732, Step 1; 60.5 mg, 0.159 mmol), Pd₂(dba)₃ (6.6 mg, 0.0069mmol), XPhos (13.8 mg, 0.029 mmol), and Na₂CO_(3(s)) (45.9 mg, 0.433mmol). After sparging the mixture with Ar_((g)), the reaction vessel wassealed. The reaction mixture was stirred for 16 h at 100° C. Aftercooling to ambient temperature, the mixture was diluted 4:1 DCM:iPrOH,and washed with water. The organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byC18 reverse-phase chromatography (5-95% ACN/water with 0.1% TFA as thegradient eluent) to afford the title compound as the TFA salt. The saltwas dissolved in 4:1 DCM:iPrOH, and extracted with saturatedNaHCO_(3(aq)). The organic extracts were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to cleanly afford the title compound(36.9 mg, 59% yield). MS (apci) m/z=466.2 (M+H).

Example 744

4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

A solution of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate (Intermediate P27; 50.1 mg, 0.139 mmol) in 4:1dioxane:water (1.4 mL) was treated with1-((6-methoxypyridin-3-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(Example 697, Step 3; 62.8 mg, 0.153 mmol), Pd₂(dba)₃ (6.4 mg, 0.0070mmol), XPhos (13.3 mg, 0.028 mmol), and Na₂CO_(3(s)) (44.2 mg, 0.417mmol). After sparging the mixture with Ar_((g)), the reaction vessel wassealed. The reaction mixture was stirred for 16 h at 100° C. Aftercooling to ambient temperature, the mixture was diluted with 4:1DCM:iPrOH, and washed with water The organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by C18 reverse-phase chromatography (5-95% ACN/water with 0.1%TFA as the gradient eluent) to afford the title compound as the TFAsalt. The salt then was diluted with 4:1 DCM:iPrOH, and treated withsaturated NaHCO_(3(aq)). The organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo to cleanly afford the titlecompound (43.6 mg, 63% yield). MS (apci) m/z=495.2 (M+H).

Abbreviations: ACN Acetonitrile AcOH Acetic Acid Boc-anhydridedi-tert-butyl dicarbonate n-BuLi n-butyllithium or 1-butyllithium s-BuOHSec-Butanol or 2-Butanol t-BuOH tert-Butanol or 2-Methylpropan-2-ol CuICopper (I) Iodide d day, days DCE 1,2-Dichloroethane DCM DichloromethaneDIEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DMFN,N-Dimethylformamide DMSO Dimethylsulfoxide EDC-HCl1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride eqequivalent Et₂O Diethyl Ether EtOAc Ethyl Acetate EtOH Ethanol GF/Fpaper GF/F glass microfiber filter paper h hour, hours HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxide hexafluorophosphate or 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxidehexafluorophosphate or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate iPrOH Isopropanol KOAc PotassiumAcetate K₂HPO₄ Potassium Phosphate, Dibasic LCMS Liquidchromatography—mass spectrometry Me₄N(AcO)₃BH TetramethylammoniumTriacetoxyborohydride NaBH(AcO)₃ Sodium Triacetoxyborohydride MeOHMethanol min minute, minutes MSH o-(mesitylsulfonyl)hydroxylamine MTBEMethyl tert-Butyl Ether NBS N-Bromosuccinimide NCS N-ChlorosuccinimideNIS N-Iodosuccinimide 10% Pd/C Palladium 10 wt. % (dry basis), activecarbon, wet, Degussa Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium (0)Pd₂(dba)3 tris(dibenzylideneacetone)dipalladium (0) PdCl₂(dppf) ·1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride CH₂Cl₂dichloromethane complex PdCl₂(PPh₃)₂Palladium(II)bis(triphenylphosphine) dichloride, PPTS Pyridiniump-toluenesulfonate PS frit Biotage ® “Isolute Phase Separators” PS paperWhatman ® silicone treated Phase Separators filter paper PVDF (0.45 μm)disc polyvinylidene difluoride membrane with a 0.45-micron pore size rtRoom temperature TBAF Tetra-n-butylammonium fluoride TEA TriethylamineTFA Trifluoroacetic acid THF tetrahydrofuran TsCl 4-Toluenesulfonylchloride Triphosgene (bis(trichloromethyl) carbonate X-phosdicyclohexyl(2’,4’,6’-triisopropyl-[1,1’-biphenyl]-2-yl)phosphine

What is claimed is:
 1. A method of treating a RET-associated cancer in asubject in need thereof, wherein the cancer has a fusion selected fromthe group consisting of: KIF5B-RET, CCDC6-RET, CLIP1-RET, PTC1ex9-RET,CEP55-RET, CUX1-RET, ACBD5-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET,MPRIP-RET, NCOA4-RET, BCR-RET, FGFR1OP-RET, MBD1-RET, PRKAR1A-RET,TRIM24-RET, KTN1-RET, GOLGA5-RET, HOOK3-RET, and KIAA1468-RET, themethod comprising administering to the subject a compound selected fromthe group consisting of:((S)-4-(6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate;4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamide;1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-carboxamide;4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate);4-(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;BLU667((1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide);and RXDX-105(1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea);or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the compound is((S)-4-(6-(4-(2-hydroxy-3-phenylpropanoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile,or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound is6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(2-(pyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile,or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the compound is4-(6-(4-(2,6-difluorobenzoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile2,2,2-trifluoroacetate, or a pharmaceutically acceptable salt thereof.5. The method of claim 1, wherein the compound is4-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N,N-diethylpiperazine-1-carboxamideor a pharmaceutically acceptable salt thereof.
 6. The method of claim 1,wherein the compound is1-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(2-methoxy-3-methylbutyl)piperidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 7. The method of claim 1,wherein the compound is4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilebis(2,2,2-trifluoroacetate), or a pharmaceutically acceptable saltthereof.
 8. The method of claim 1, wherein the compound is4-(6-(4-(2,6-difluorobenzyl)piperazin-1-yl)pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile,or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1,wherein the compound is4-(6-(4-(2-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile,or a pharmaceutically acceptable salt thereof.
 10. The method of claim1, wherein the compound is6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridine-2-ylmethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile,or a pharmaceutically acceptable salt thereof.
 11. The method of claim1, wherein the compound is4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile,or a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the compound is BLU667((1s,4R)-N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide),or a pharmaceutically acceptable salt thereof.
 13. The method of claim1, wherein the compound is RXDX-105(1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea),or a pharmaceutically acceptable salt thereof.